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European Pharma Summit

2017-11-192017-10-162017-09-16
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Day 1 - Thursday, November 16th, 2017
8:00
Registration & Breakfast at Restaurant (included for those staying at the Radisson Blu)
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8:50
Welcome & Opening Remarks
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10:55
Morning Networking Break
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Drug Design & Medicinal Chemistry
Tools and Technologies for Drug Discovery
Moderator: Ingo Mugge, Alkermes
11:25
Medicinal Chemistry Optimizations in Deep Water: SAR Studies on mGluR5 Allosteric Modulators
 
György  Keserű
György Keserű
Principal Investigator, Medicinal Chemistry
Hungarian Academy of Sciences
About Speaker: György M. Keserű obtained his Ph.D. at Budapest, Hungary and joined Sanofi-Aventis CHINOIN heading a chemistry research lab. He moved to Gedeon Richter in 1999 as the Head of Computer-aided Drug Discovery. He earned D.Sc. from the Hungarian Academy... Read Full Bio 
 
 
György  Keserű
György Keserű
Principal Investigator, Medicinal Chemistry
Hungarian Academy of Sciences
 
About Speaker:

György M. Keserű obtained his Ph.D. at Budapest, Hungary and joined Sanofi-Aventis CHINOIN heading a chemistry research lab. He moved to Gedeon Richter in 1999 as the Head of Computer-aided Drug Discovery. He earned D.Sc. from the Hungarian Academy of Science in 2003 and he was invited for a research professorship at the Budapest University of Technology and Economics. Since 2007 he was appointed as the Head of Discovery Chemistry at Gedeon Richter. He served as a director general of the Research Centre for Natural Sciences (RCNS) at the Hungarian Academy of Sciences. He contributed to the discovery of the antipsychotic Vraylar® (cariprazine) that has been approved by the US FDA in 2015 and marketed in the US from 2016. From 2015 he is heading the Medicinal Chemistry Research Group at RCNS. His research interests include medicinal chemistry, drug design, and in silico ADME. He has published over 200 papers and more than 10 books and book chapters.

 
Abstract: Potency optimizations are typically i...Read More 

Potency optimizations are typically involving the formation of new interactions between the ligand and its protein target. In many cases, however, ligand-protein interactions are water mediated that makes SAR analyses extremely. This situation could be even more challenging when the potency gain is mostly traced back to the displacement of energetically unfavoured waters and/or the perturbation of water networks in the binding pocket. Targeting functional water channels as allosteric sites in GPCRs is a typical example for such a challenging optimization. As a prototype study we investigate different mGluR5 NAM programs analysing the optimization path and SAR in the context of water mediated interactions formed during the potency optimization of these chemotypes. The optimization of allosteric mGluR5 ligands is notoriously difficult and is complicated by minor structural changes induced NAM-PAM switch. The allosteric site of the mGlu5 receptor is located in a functional water channel. The binding pocket is therefore occupied by water molecules that are at least partially ordered and play a role in signal transduction. The perturbation of this water network by allosteric ligands contributes significantly to the observed ligand affinity and functional activity. This phenomenon severely compromises the success of SAR studies. We show that an improved interpretation of SAR can be achieved by considering the reorganization of the water network upon complex formation. Ligand binding leads to the expulsion of water molecules and the free-energy consequence of the binding is affected by this process. Moreover, ligand binding changes the free-energy of the water network that remains in the binding pocket and the effect of this perturbation can also significantly influence the observed ligand affinity. The importance of the water molecules is therefore also reflected by the difference in the free-energy change of the water network corresponding to the binding of ligands as their activity improves from micromolar to high nanomolar. This observation supports that ligand-protein interactions are not the only factors and even they are not decisive for the binding of these ligands. However, the presence of a favourable water network and optimized ligand-protein interactions are both required to achieve high activity on mGluR5 receptor.

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GPCR Targeted Screening
Screening Technologies for GPCRs
Moderator: Davide Calebiro, University of Birmingham, University of Würzburg
11:25
Photopharmacology: Spatiotemporal Control of Native Receptors in vivo with Allosteric Photoswitchable Ligands
 
Amadeu  Llebaria
Amadeu Llebaria
Director, Medicinal Chemistry & Synthesis
Spanish National Research Council
About Speaker: Amadeu Llebaria is head of the MCS group  at IQAC-CSIC Research Institute in Barcelona (Spain). Amadeu is a chemist and has been working in design and synthesis of organic molecules, medicinal chemistry and chemical biology both in basic science and... Read Full Bio 
 
 
Amadeu  Llebaria
Amadeu Llebaria
Director, Medicinal Chemistry & Synthesis
Spanish National Research Council
 
About Speaker:

Amadeu Llebaria is head of the MCS group  at IQAC-CSIC Research Institute in Barcelona (Spain). Amadeu is a chemist and has been working in design and synthesis of organic molecules, medicinal chemistry and chemical biology both in basic science and industrial applications. He is now interested in the development of radically new approaches for drug therapeutics. Working in the borderline of chemistry, biology and biophysics he is involved in glycolipid immunotherapeutics, chemical methods for endogenous protein labelling and the use of light for the precise control of protein and receptor activity with photoswitchable ligands.  

 
Abstract: The administration of a photocontroll...Read More 

The administration of a photocontrolled ligand in combination with illumination that is patterned in space and time can provide a novel degree of control and regulation of receptor activity. This method would allow focusing the action of the ligand, controlling the location and the temporal extension of its effects. When applied in vivo, the use of photoregulation can reduce side effects by targeting receptors located in specific tissues, establishing personalized drug schedules to patient needs.

We will describe azobenzene and azopyridine allosteric ligands for metabotropic glutamate receptors that allow the real-time photoregulation  of receptors in cells and living animals and can be extended to the  precise control of physiology, including localized on/off activation in the  mice brain of a peripheral pain stimulus.

This approach is effective to study the pharmacology of mGluRs and shows potential for spatiotemporal regulation of drugs targeting this GPCR family of receptors.

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Kinase Inhibitors in Drug Discovery
Technological Advances for Studying the Kinome
Moderator: Guido Zaman, Netherlands Translational Research Center
11:25
Computational Approaches to Study Kinase Regulation and Function
 
Pedro  Beltrao
Pedro Beltrao
Group Leader
EMBL-EBI
About Speaker: PhD in Biology, University of Aveiro (research conducted at EMBL-Heidelberg), 09/2007. Postdoctoral research at the University of California San Francisco. Group leader at EMBL-EBI since 2013.... Read Full Bio 
 
 
Pedro  Beltrao
Pedro Beltrao
Group Leader
EMBL-EBI
 
About Speaker:

PhD in Biology, University of Aveiro (research conducted at EMBL-Heidelberg), 09/2007. Postdoctoral research at the University of California San Francisco. Group leader at EMBL-EBI since 2013.

 
Abstract: Protein kinases are crucial component...Read More 

Protein kinases are crucial components of cell decision circuits that are often dysregulated in disease. They constitute one of the largest protein families in the human genome but additional effort is needed to develop comprehensive approaches to study kinase specificity, substrate identification, function and regulation across conditions and disease. We have been working on computational methods to address these aspects of kinase biology. In this presentation I will focus on our efforts to estimate kinase activity from phosphoproteomic data and on the identification of copy number aberrations in cancer that are linked to changes in kinase signalling. We and others have shown that kinase activity changes across conditions can inferred from statistical analyses of phosphoproteomic data. We are using these methods to infer kinase activity regulation in cancer samples and to identify genomic alternations that are associated with such changes. We believe this work will facilitate the identification of potential kinase targets for treatment of cancer sub-types.

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11:50
High Content Analysis-Based Exploration of Steroid Receptor Functions
 
Michael Mancini
Michael A. Mancini
Professor, Molecular and Cellular Biology
Baylor College of Medicine
About Speaker: The Mancini lab focuses upon single cell analysis of steroid receptor functions, primarily estrogen and androgen receptors (ER, AR), and attendant coregulators. Our HCA/HCS-based projects explore cell signaling, endocrine disrupting chemicals and epi... Read Full Bio 
 
 
Michael Mancini
Michael A. Mancini
Professor, Molecular and Cellular Biology
Baylor College of Medicine
 
About Speaker:

The Mancini lab focuses upon single cell analysis of steroid receptor functions, primarily estrogen and androgen receptors (ER, AR), and attendant coregulators. Our HCA/HCS-based projects explore cell signaling, endocrine disrupting chemicals and epigenetics at the single cell level in engineered and native cultured cells.

 
Abstract: The Mancini lab utilizes single cell-...Read More 

The Mancini lab utilizes single cell-oriented imaging studies to study transcriptional activity of primarily estrogen receptor and androgen receptors in highly multiplexed, high content assays/screens.  The lab has developed high throughput microscopy and image informatics approaches to study receptor functions, including a program to evaluate and classify endocrine disrupting chemicals (EDCs), including bisphenol A and analogs thereof.  The overall high content analysis-based screening approaches have been used to also perform mRNA FISH for receptor targets, and nuclear receptor coregulator siRNA screens that identified a novel ubiquitin ligase as a key regulator of ER functions.  High throughput approaches have also been used to better enable monoclonal antibody development, including use of HCA to identify hits in primary hybridoma screens using conditions of the desired end assay (e.g., immunofluorescence, IHC, mRNA FISH, immunogold, etc), greatly surpassing the value of ELISA-driving screening.  

Benefits:
1. learn about benefits of single cell analysis in transcription assays
2. learn about issues of heterogeneity (transcription factor levels vs transcriptional output)
3. learn about sensitive, multiplexed endocrine disrupting chemical assays
4. learn about epigenetic issues that are linked to how many endogenous large gene alleles actively respond to hormone

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11:50
The Kinetics of Drug-Receptor Binding: Why it is Important and how can we Measure it
 
David  Sykes
David Sykes
Scientific Officer
University of Nottingham
About Speaker: David Sykes has over 20+ years of experience working in a drug discovery environment mainly in a specialist assay development role and most recently with Novartis. During this period David has made a significant contribution to the understanding of a... Read Full Bio 
 
 
David  Sykes
David Sykes
Scientific Officer
University of Nottingham
 
About Speaker:

David Sykes has over 20+ years of experience working in a drug discovery environment mainly in a specialist assay development role and most recently with Novartis. During this period David has made a significant contribution to the understanding of agonist/ antagonist GPCR kinetic determinants resulting in a number of high impact publications in an area of growing scientific interest. David is currently employed as an Experimental Officer by The University of Nottingham and studying for a PhD in Molecular Pharmacology and Drug Discovery.. David has recently taken up a new position at the University working in a group led by Prof. Dmitry Veprintsev. His current interests include the development of HTS fluorescence-based kinetic binding assays specifically designed to assess the kinetics of unlabelled compounds and chemical fragments and the use of purified receptor proteins as tools for drug discovery.

 
Abstract: It is becoming more widely appreciate...Read More 

It is becoming more widely appreciated that the kinetics of drug-receptor binding plays an important role in dictating both pharmacological and clinical drug properties. This has led to an increasing interest in quantifying binding kinetics earlier in the drug discovery screening cascade. The competition-association binding method is a widely used approach to assess the kinetic parameters of unlabelled compounds, however the traditional radioligand binding techniques are low throughput and environmentally unfriendly. To address this we have developed and validated a time-resolved fluorescence resonance energy transfer (TR-FRET) method with significantly improved throughput. This presentation will address the key factors critical for accurate parameter estimation and demonstrate the potential of this method to serve as a platform for the screening of large fragment libraries. Additionally I will discuss with examples the benefit of assessing and optimising kinetic parameters early on in the development of future therapeutics.

Benefits:

• Realise the benefit of early kinetic optimisation in the lead optimisation phases of your drug discovery program.

• See first-hand through real-life examples the significant increase in assay throughput offered by employment of homogenous time-resolved fluorescence (HTRF) technology.

• Understand the factors critical to the estimation of unlabelled compound kinetic parameters using the competition association assay approach.

• Discover the latest approaches to modelling the actions of drugs in the CNS using in-vitro derived kinetic parameters.

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11:50
Allosteric Inhibitor Discovery with Aurora A Kinase and Second-Harmonic Generation (SHG)
 
Joshua Salafsky
Joshua Salafsky
Founder and Chief Scientific Officer
Biodesy Inc.
About Speaker: Josh is the Founder of Biodesy and the inventor of the Second Harmonic Generation (SHG) technique for studying biological molecules. Josh was awarded a number of NSF and NIH grants and obtained key scientific breakthroughs that galvanized the scienti... Read Full Bio 
 
 
Joshua Salafsky
Joshua Salafsky
Founder and Chief Scientific Officer
Biodesy Inc.
 
About Speaker:

Josh is the Founder of Biodesy and the inventor of the Second Harmonic Generation (SHG) technique for studying biological molecules. Josh was awarded a number of NSF and NIH grants and obtained key scientific breakthroughs that galvanized the scientific and venture capital communities.  Previously, Josh was a postdoctoral fellow in the Dept. of Chemistry at Columbia University and the Dept. of Physics at Utrecht University in the Netherlands, as well as a guest researcher at the Cavendish Laboratory at the University of Cambridge, UK. His expertise and interests are in the areas of Biophysics and Physical Chemistry. At Biodesy he leads a team focused on creating novel techniques with SHG and applying them to problems in drug discovery and structural biology.  Josh received his PhD from Stanford University where he studied the reaction center protein, the marvelous engine at the heart of photosynthesis which converts light into chemical energy.

 

 
Abstract: The catalytic domains around the ATP-...Read More 

The catalytic domains around the ATP-binding pocket of all known kinases are remarkably similar, which accounts for the fact that many kinase inhibitors lack selectivity. Targeting allosteric sites distal to the kinase ATP-binding pocket is a promising therapeutic approach to circumvent this issue. Allosteric inhibitors must modulate the target conformation to be effective, but traditional methods cannot directly identify them. Here we present a novel approach to identify inhibitors of protein kinase Aurora A using a method based on second-harmonic generation, a nonlinear optical method that is highly sensitive to conformational changes in real time and at high throughput.  We present data on a robust, optimized SHG assay to screen for compounds that cause allosteric changes in Aurora A.  In a screen of the Maybridge 2500 Ro3 fragment library we have identified 100 compounds that promote distinct conformational changes in the protein in the presence of ADP.  Further study of these compounds is currently underway.  We hope the compounds reveal novel allosteric mechanisms and prove useful as tools for studying the structure-function relationship in Aurora A.

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12:15
Halogen-Enriched Fragment Libraries (HEFLibs) - A Tool for Studying Halogen Bonding
 
Frank  Boeckler
Frank Boeckler
Professor, Pharmacy and Biochemistry
Eberhard Karls Universität Tübingen
About Speaker: Frank M. Boeckler received his Ph.D. in Medicinal Chemistry at the University of Erlangen (Germany) in 2004 under supervision of Prof. Peter Gmeiner. He specialized in computational chemistry and drug design, ranging from QM methods to in silico scre... Read Full Bio 
 
 
Frank  Boeckler
Frank Boeckler
Professor, Pharmacy and Biochemistry
Eberhard Karls Universität Tübingen
 
About Speaker:

Frank M. Boeckler received his Ph.D. in Medicinal Chemistry at the University of Erlangen (Germany) in 2004 under supervision of Prof. Peter Gmeiner. He specialized in computational chemistry and drug design, ranging from QM methods to in silico screening. In 2006, he joined Prof. Sir Alan R. Fersht at the MRC Center for Protein Engineering in Cambridge/UK as Marie Curie fellow and discovered there p53 mutant stabilizers as potential new cancer therapeutics. While working in Cambridge at the interface of experiment and theory, he focused on molecular biology and biophysics. In 2008, he was appointed as Professor (W2tt) for Bioanalytics at Ludwig-Maximilians University (LMU) Munich. In 2010, he moved to Eberhard Karls University Tuebingen as Professor for Medicinal Chemistry/Drug Design. He is head of the laboratory of Molecular Design & Pharmaceutical Biophysics, which combines chemical biology, molecular and structural biology and biophysics, as well as computational chemistry and molecular design. His work is dedicated to understanding molecular interactions as the foundation for chemical biology and drug discovery, to apply theoretical and biophysical methods to cancer research, and to develop novel peptide-based toolkits. Since 2014, he is also member of the Center of Bioinformatics (ZBIT) of the University of Tuebingen. In 2015 he has joined the team of editors of the RÖMPP Encyclopedia covering the area of Pharmacy and Medicine. He has received multiple awards, including the Klaus-Grohe prize in Medicinal Chemistry, as well as the European Federation of Medicinal Chemistry (EFMC) Young Medicinal Chemist in Academia Prize (2016).

 
Abstract: With the popularity of halogen bondin...Read More 

With the popularity of halogen bonding on the rise, particularly in life sciences and drug discovery [1], there is an increasing demand for understanding the complexity and versatility of these interactions. Halogen bonds are favorable, fairly directional interactions between an electropositive region on the halogen, the sigma hole, and a number of different nucleophilic interaction partners. Some aspects of halogen bonding are not yet understood well enough to take full advantage of its potential in drug discovery. In this talk, I will present the concept of halogen-enriched fragment libraries (HEFLibs). These libraries consist of chemical probes, facilitating the identification of favorable halogen bonds by sharing the advantages of classical fragment-based screening. We have applied the HEFLibs concept to finding p53 mutant stabilizers [2], yielding a series of molecular probes that show a robust binding mode featuring one of the strongest halogen bonds towards a backbone carbonyl in the entire PDB [3]. In order to optimize the diversity of HEFLibs, we have invented a feature tree-based similarity assessment guiding the diversification of fragment chemotypes, binding motifs and halogen bonding strengths. We achieve a fast and efficient implementation of tuning effects into the diversity selection by a machine-learned model. Such diversity-optimized HEFLibs are valuable tools for studying the strength and tunability of halogen bonds, while likewise allowing to investigate chemical and metabolic stability in a scaffold-dependent and substituent-specific manner [4]. Furthermore, binding motifs involving halogen bonds can be used for improving our understanding of cooperativity and specificity in molecular recognition processes in the binding site. Besides providing insights into the nature and applicability of halogen bonding, halogen-enriched fragment libraries provide smart starting points for hit-to-lead evolution. I will summarize some recent projects in which HEFLibs were applied to typical drug targets. References: [1] J Med Chem 2013, 56, 1363-1388. [2] J Am Chem Soc 2012, 134, 6810-6818. [3] J Chem Inf Model 2015, 55, 687-699. [4] Future Med Chem 2014, 6, 617-639.

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12:15
The Confobody Technology, A New Platform to Enable Fragment Screening on GPCRs
 
Christel Menet
Christel Menet
Chief Scientific Officer
Confo Therapeutics
About Speaker: Born in 1975 in France, Christel received an MPhil. in 1999 and a Ph.D. in 2002 both in organic chemistry at the Manchester University, in the UK. During her Ph.D., she was author of 8 publications. She then started her industrial carrier at EvotecOA... Read Full Bio 
 
 
Christel Menet
Christel Menet
Chief Scientific Officer
Confo Therapeutics
 
About Speaker:

Born in 1975 in France, Christel received an MPhil. in 1999 and a Ph.D. in 2002 both in organic chemistry at the Manchester University, in the UK. During her Ph.D., she was author of 8 publications. She then started her industrial carrier at EvotecOAI, where she developed her expertise in parallel synthesis. Quickly, she joined Faust pharmaceuticals for a new position in 2004, where she did her initiation to medicinal chemistry and neurodegerative diseases, looking for active drugs for mGluRs. She then moved to new challenges at Galapagos. Her carrier at Galapagos was paved with successes including the discovery of 6 active small molecules, which moved to preclinical studies. 3 compounds were tested in phase I clinical trial with a positive proof of mechanism. From these 3, 2 are currently in phase II, GLPG0778 and GLPG0634. The two compounds already showed promising results, Psoriasis for GLPG0778 and RA for GLPG0634. GLPG0634 was the first selective JAK1 inhibitor in clinical trials in inflammatory and auto-immune conditions. She is today CSO of a spin-off company, Confo Therapeutics and she is inventor of more than 20 patents.

 
Abstract: The G-protein coupled receptor (GPCR)...Read More 

The G-protein coupled receptor (GPCR) superfamily is the largest known class of molecular targets with proven therapeutic value, since about 30–40% of all approved drugs act on GPCRs. In the last 30 years, GPCR drug discovery has relied on radioligand binding or reporter cell-based assays combined with high-throughput screening (HTS) of large compound libraries for hit discovery. However, progress in identifying new small molecule drugs has been difficult and disappointing especially for GPCR agonists. One first problem is that compounds do not only need to bind to the GPCR, but they must also exhibit the appropriate efficacy profile: agonist, partial agonist, neutral antagonist or inverse agonist. A second key hurdle is often the chemical space covered by the chemical library does not yield hits on GPCRs.

In 2000 the first crystal structure of a class A GPCR, rhodopsin, was published. Recent insight into GPCR structure have greatly enhanced the understanding of the molecular mechanisms of activation and constitutive activity of these receptors, and have enabled the use of structure-based drug design techniques to be applied to the target class for the first time. Implementation of the modern paradigm of FBDD in the GPCR field has lagged significantly behind soluble protein target classes, primarily because GPCRs typically suffer from low expression and poor stability. Different approaches have now being developed to stabilised these proteins outside the membrane and allow the use of biophysical technics like SPR or NMR for screening.

Confobodies,  small (15 kDa) and stable single domain fragments harbouring full antigen-binding capacity, recognize discontinuous amino acid segments on native proteins, making them ideal tools to selectively stabilize specific conformational states of (membrane) proteins. Confo Therapeutics’ approach, based on this technology, is developing a Confobody-enabled drug discovery platform to explore new chemical space for the development of new drugs targeting GPCRs. Confobodies enable screening of a fragment library leading to the discovery of new chemical entities presenting several advantages.

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12:15
Systems Biology of Oncogenic Signalling
 
Pedro  Cutillas
Pedro Cutillas
Reader in Cell Signalling & Protoemics, Barts Cancer Institute
Queen Mary University of London
About Speaker: Group Leader at Barts Cancer Institute since 2007, Previously at Ludwig Institute, and University College London... Read Full Bio 
 
 
Pedro  Cutillas
Pedro Cutillas
Reader in Cell Signalling & Protoemics, Barts Cancer Institute
Queen Mary University of London
 
About Speaker:

Group Leader at Barts Cancer Institute since 2007, Previously at Ludwig Institute, and University College London

 
Abstract: Kinase inhibitors are one of the majo...Read More 

Kinase inhibitors are one of the major classes of anticancer drugs and are revolutionizing the way most tumour types are treated. However, not all cancer patients respond to kinase inhibitors to the same extent and most of those who initially respond eventually develop resistance. Current models used to rationalize responses, such as the oncogene addiction paradigm, do not always explain such resistance phenotypes. Using the PI3K/Akt/mTOR pathway as a model of oncogenic signalling, much of our recent work has been directed at advancing our understanding of why some tumours respond to targeted therapies while others are resistant. To this end, we first optimized technology for label-free phosphoproteomics and for deriving information on kinase activity from phosphoproteomics data. Taking leukaemia as a proof-of-concept, we found that the activities of pathways acting in parallel to PI3K determine whether or not leukaemia cells may respond to PI3K inhibitors. Modelling of phosphorylation data predicted sensitivity to several inhibitors of cell signalling with very high accuracy. As an extension of this work, we recently found that the activation status of MAPK, STAT and PKCdelta signalling pathways determine the extent by which leukaemia cells respond to MEK and FLT3 inhibitors. Together, these data suggest that technology for measuring the signalling network as a whole (rather than just the target pathway) will be needed in order to accurately predict which patients may benefit from treatments based on inhibitors against PI3K and MAPK pathway members.

Benefits
– Technology to quantify kinase signalling pathways and for personalized medicine
– Approach to rank kinases based on their contribution to cancer biology
– Determination of mechanisms of intrinsic resistance to kinase inhibitors
– Combination of target and parallel pathway activity determines response to kinase inhibitors

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12:40
New Directions in DNA-Encoded Chemistry Through a Tailored Encoding Strategy
 
Andreas  Brunschweiger
Andreas Brunschweiger
Research Group Leader, Chemistry & Chemical Biology
TU Dortmund
About Speaker: Andreas Brunschweiger studied pharmacy at the University of Kiel (Germany), and joined the group of Prof. Christa Müller at the University of Bonn (Germany) to obtain his Ph.D. After conducting postdoctoral research in the same group in a collaborat... Read Full Bio 
 
 
Andreas  Brunschweiger
Andreas Brunschweiger
Research Group Leader, Chemistry & Chemical Biology
TU Dortmund
 
About Speaker:

Andreas Brunschweiger studied pharmacy at the University of Kiel (Germany), and joined the group of Prof. Christa Müller at the University of Bonn (Germany) to obtain his Ph.D. After conducting postdoctoral research in the same group in a collaboration project with UCB Pharma to develop small molecule inhibitors for targets associated with neurodegenerative diseases, he joined Prof. Jonathan Hall's research group at the Institute of Pharmaceutical Sciences of the ETH Zurich (Switzerland) in 2010. There, he was involved in the the development of a chemical biology strategy to identify target RNAs of microRNAs, and the design and synthesis of oligonucleotides as microRNA inhibitors. In 2013 he took up his present position as a group leader at the Faculty of Chemistry and Chemical Biology at the TU Dortmund University. His current research interests include the development of new synthesis and encoding strategies that allow for expanding the chemical space of DNA-encoded small molecule screening libraries.

 
Abstract: DNA-encoded compound libraries (DELs)...Read More 

DNA-encoded compound libraries (DELs) have found widespread use as screening technology for drug research.[1,2] Tagging compounds with genetic information allows for synthesis and handling of very large screening collections of drug-like small molecules as complex mixtures. These compound mixtures are screened efficiently on disease-relevant target proteins by selection. Bioactive compounds are identified from a screen by PCR-amplification of the genetic information and next generation sequencing of the amplicon mixtures.

Heterocycles are essential structures in the chemical space of bioactive compounds. Transition metal catalysts, and acid organocatalysts enable access to diverse drug-like heterocycles from simple starting materials, but interact or even react with purine bases eventually causing depurination of the DNA tag. To circumvent this impediment to methods development for DELs, we utilize a hexathymidine sequence “hexT” as an adapter oligonucleotide in the initial step of DEL synthesis (Figure 1).[3] The hexT tolerated several catalysts and harsh reaction conditions for target heterocycle synthesis that are usually not reconcilable with DNA. The hexT-heterocycle conjugates were readily ligated to coding DNA sequences with a hexa-adenosine overhang.

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12:40
Integration of GPCR Signaling and Sorting from Very Early Endosomes via Opposing APPL1 Mechanisms
 
Silvia Sposini
Silvia Sposini
Ph.D. Student
Imperial College London
About Speaker: Dr. Silvia Sposini recently finished her PhD at Imperial College London, where she has worked in Dr. Aylin Hanyaloglu’s lab investigating the intracellular trafficking and signalling of the Luteinzing hormone receptor. Throughout her academic caree... Read Full Bio 
 
 
Silvia Sposini
Silvia Sposini
Ph.D. Student
Imperial College London
 
About Speaker:

Dr. Silvia Sposini recently finished her PhD at Imperial College London, where she has worked in Dr. Aylin Hanyaloglu’s lab investigating the intracellular trafficking and signalling of the Luteinzing hormone receptor. Throughout her academic career she has been focused on GPCRs, looking at different regulatory mechanisms of their activity. Before joining Imperial College, she worked on Prokineticin receptor dimerization at “Sapienza” University of Rome, from  where she obtained both her BSc and MSc degrees (cum laude) in 2010 and 2013, respectively. She has received a number of prizes and scholarships, including the recently awarded Society for Endocrinology Early Career Grant with a project on the effect of allosteric modulators on the spatio-temporal activity of GPCRs.

 
Abstract: Endocytic trafficking is a critical m...Read More 

Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Employing luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, and additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling, without impacting the EE-localized b2-adrenergic receptor. LHR recycling is driven by receptor-mediated Gas/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. Receptor/Gas endosomal signaling is localized to microdomains of heterogeneous VEE populations, and regulated by APPL1 phosphorylation. Our study uncovers a highly integrated inter-endosomal communication system, enabling cells to tightly regulate spatially-encoded signalling.

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12:40
Can CRISPR/Cas9 Discover New Synthetic Lethal Kinase Targets for Undruggable Cancer Drivers?
 
Paul Russell
Paul Russell
Senior Scientist, Therapeutic R&D
Horizon Discovery Ltd
About Speaker: Since 2012 Paul Russell has had a Senior Scientist role within Horizon Discovery’s Target Validation and Drug Discovery efforts. He has been using gene manipulation techniques, such as CRISPR & siRNA, to identify & validate synthetic lethal... Read Full Bio 
 
 
Paul Russell
Paul Russell
Senior Scientist, Therapeutic R&D
Horizon Discovery Ltd
 
About Speaker:

Since 2012 Paul Russell has had a Senior Scientist role within Horizon Discovery’s Target Validation and Drug Discovery efforts. He has been using gene manipulation techniques, such as CRISPR & siRNA, to identify & validate synthetic lethal targets associated with common cancer mutations. Prior to this, he spent 18 years in the University of Cambridge; first with Prof Bruce Ponder studying BRCA genetics and then with Prof Ashok Venkitaraman investigating factors that influence the outcome of a drug induced mitotic arrest.

 
Abstract: Kinase targets have provided many of ...Read More 

Kinase targets have provided many of the most significant new oncology medicines of the last 20 years. Generally the targets successfully drugged have been tyrosine kinases that act as direct oncogenic drivers in mutated or translocated forms, or that influence angiogenesis. One front of kinase drug discovery has advanced to target rarer and rarer mutations in drivers, while another has focussed on kinase targets downstream of undruggable oncogenes such as KRAS. Generally, the first has met more success.

A third line of kinase drug discovery has focussed on synthetic lethality. These efforts have targeted kinases such as CHEK1, which emerged from fission yeast biology and STK33 and TBK1, which emerged from RNA interference screens aimed at finding targets only required in KRAS mutant cells. As is now well appreciated, there are significant issues with RNA interference as a screening technology: False negatives are common as only partial knockdown is possible, leading sometimes to low penetrance phenotypes, and false positives are also an issue due to off target effects.

The study of immune responses in bacteria has led to the recent identification of an RNA programmable nuclease, CRISPR/Cas9, and researchers have been quick to adapt this technology to genome wide screens. CRISPR /Cas9 overcomes some of the issues of RNA interference, as it can generate all-allelic null mutations and appears to have fewer off target effects.

Horizon Discovery has used CRISPR/Cas9 to perform looked screens of a 3000 gene library (10 sgRNA/gene) that includes protein and lipid kinases against a panel of some 35 cell lines predominantly derived from colon and lung cancers. This allows definition of which kinases are members of the essentialome, which includes CHEK1 and other kinases in the DNA damage response implying potentially narrow therapeutic windows. The literature KRAS synthetic lethal candidates derived from RNA interference screens were not confirmed, but we have identified novel candidates selectively required in the KRAS or TP53 mutant cohort. These have been further validated in ultra-deep CRISPR screens that highlight hot spots in the amino acid sequences where even in frame indels have catastrophic consequences for protein function.

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13:05
Lunch Provided by GTCbio for All Attendees || Lunch with Mentors (RSVP only)
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Drug Design & Medicinal Chemistry
Novel Computational Methods & Predictive Models
Moderator: Anna K. H. Hirsch, Helmholtz Institute for Pharmaceutical Research Saarland
14:30
Rationalizing the Membrane Permeability of Cyclic Peptides
 
Sereina  Riniker
Sereina Riniker
Professor, Physical Chemistry
ETH Zurich
About Speaker: Sereina Riniker has been an Assistant Professor (with tenure track) of Computational Chemistry at the Laboratory of Physical Chemistry since June 2014. She was born in Switzerland in 1985. In 2008, she completed her master’s degree in chemistry a... Read Full Bio 
 
 
Sereina  Riniker
Sereina Riniker
Professor, Physical Chemistry
ETH Zurich
 
About Speaker:

Sereina Riniker has been an Assistant Professor (with tenure track) of Computational Chemistry at the Laboratory of Physical Chemistry since June 2014.

She was born in Switzerland in 1985.

In 2008, she completed her master’s degree in chemistry at ETH Zurich, with a research project at the Autonomous University of Barcelona with Prof. Xavier Daura. After an internship in the research department of Givaudan AG and a research stay in the group of Prof. Berend Smit at UC Berkeley, she returned in 2009 to ETH Zurich to obtain a PhD in molecular dynamics simulations with Prof. Wilfred van Gunsteren.

From 2012 to 2014, she held a postdoctoral position in cheminformatics under the supervision of Dr. Gregory Landrum at the Novartis Institutes for BioMedical Research in Basel and Cambridge, Massachusetts.

 
Abstract: The hypothesis for the passive membra...Read More 

The hypothesis for the passive membrane permeability of cyclic peptides involves the interconversion between open conformations (with the backbone amides positioned for hydrogen bonds with the solvent), and closed conformations (with intramolecular backbone hydrogen bonds) prior to the entering of the membrane. Kinetic models based on multi-microsecond molecular dynamics (MD) simulations of the natural product cyclosporine A and its synthetic derivative cyclosporine E in polar and apolar environments reveal that, although similar open and closed conformational states exist, the interconversion rates between them differ substantially for the two peptides. Furthermore, an additional half-opened congruent state was observed for cyclosporine A, which was not present with cyclosporine E. These observations offer a rational for the difference in membrane permeability between cyclosporine A and E by one order of magnitude. These findings are supported by the good qualitative agreement between the kinetic models and the experimental NMR data. The workflow is further applied to a recently published series of cyclic decapeptides, which a backbone skeleton specifically designed for inherent passive membrane permeability. These structurally closely related peptides exhibit different degrees of permeability and solubility. Using our kinetic models, a rational for the observed differences is provided.

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GPCR Targeted Screening
GPCR Signaling Pathways and Mechanisms
Moderator: Kirill Martemyanov, The Scripps Research Institute
14:30
Single-Molecule Imaging of GPCR Signaling
 
Davide  Calebiro
Davide Calebiro
Professor, Molecular Endocrinology; Principal Investigator
University of Birmingham; University of Würzburg
About Speaker: Davide Calebiro is a Professor of Molecular Endocrinology at the Institute of Metabolism and Systems Research (IMSR) of Birmingham University. Prof. Calebiro studied Medicine in Milan and Stockholm and obtained a Clinical Specialization in Endocrinol... Read Full Bio 
 
 
Davide  Calebiro
Davide Calebiro
Professor, Molecular Endocrinology; Principal Investigator
University of Birmingham; University of Würzburg
 
About Speaker:

Davide Calebiro is a Professor of Molecular Endocrinology at the Institute of Metabolism and Systems Research (IMSR) of Birmingham University. Prof. Calebiro studied Medicine in Milan and Stockholm and obtained a Clinical Specialization in Endocrinology and Metabolic Diseases as well as a PhD in Molecular Medicine from the University of Milan. Since 2009, he has been leading a research group at the Institute of Pharmacology and Bio-Imaging Center of Würzburg University, Germany. His group investigates the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in human disease, which they elucidate using innovative biophysical techniques, such as FRET, single-molecule microscopy and various superresolution microscopy methods. His major contributions include the discovery that GPCRs are not only active at the plasma membrane but also at intracellular sites and that these receptors interact among themselves and with other membrane proteins to form dynamic nanodomains at the plasma membrane.

 
Abstract: G protein-coupled receptors (GPCRs) a...Read More 

G protein-coupled receptors (GPCRs) are the largest family of cellular receptors. They mediate the effects of several hormones and neurotransmitters and represent major pharmacological targets. In our lab we are developing single-molecule microscopy methods to investigate the organization of GPCR signaling cascades at the surface of living cells. Using this approach, we could show that three prototypical GPCRs have very different localization, mobility and tendencies to form supramolecular complexes. The formation of such complexes is due to transient receptor-receptor interactions, which can be directly visualized with our approach. Interactions between receptors and the underlying cytoskeleton seem to play an important role in defining the spatial arrangement of receptors. More recently, we have extended this approach to investigate the interactions between receptors and G proteins at single-molecule level. Our results reveal that GPCR signaling cascades are at the same time very dynamic and yet highly organized in space and time. These data suggest the existence of dynamic receptor nanodomains on the cell surface, which appears required for achieving high signaling efficiency and specificity.

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Kinase Inhibitors in Drug Discovery
Novel & Alternative Approaches in Drug Discovery
Moderator: Jon Elkins, State University of Campinas
14:30
Discovery of Allosteric Inhibitors for Focal Adhesion Kinase
 
Daniel  Lietha
Daniel Lietha
Group Leader, Cell Signalling and Adhesion Group
Spanish National Cancer Research Centre (CNIO)
About Speaker: Daniel Lietha received his undergraduate degrees in Chemistry in 1995 and Biotechnology in 1996 from the Zurich University of Applied Sciences (Switzerland). In 1998 he obtained his masters degree in Biotechnology from Teesside University (UK). In 20... Read Full Bio 
 
 
Daniel  Lietha
Daniel Lietha
Group Leader, Cell Signalling and Adhesion Group
Spanish National Cancer Research Centre (CNIO)
 
About Speaker:

Daniel Lietha received his undergraduate degrees in Chemistry in 1995 and Biotechnology in 1996 from the Zurich University of Applied Sciences (Switzerland). In 1998 he obtained his masters degree in Biotechnology from Teesside University (UK). In 2003 he obtained his PhD degree in Protein Crystallography from Birkbeck College (UK). The research project for his PhD he carried out at the MRC Laboratory of Molecular Biology, Cambridge (UK), under the supervision of E. Gherardi working on Hepatocyte growth factor and its Met receptor. For his postdoctoral training he joined the laboratory of M.J. Eck at the Dana-Faber Cancer Institute, Harvard Medical School, Boston (USA) where he worked on signalling mechanisms involved in cell-matrix adhesion, which led to a seminal contribution on the structure and regulation of Focal Adhesion Kinase. In September 2009 Daniel Lietha joined the CNIO as a Junior Group Leader in the Structural Biology and Biocomputing Programme. In 2011 he was granted a Ramón y Cajal Research Fellowship from the Spanish ministry. His research focuses on the structure and regulation of proteins involved in cellular growth and adhesion signalling. He aims to obtain atomic-level insights into detailed regulatory mechanisms. Further, he utilises structural and mechanistic insights to guide the discovery of small-molecule ligands that target these regulatory mechanisms. Such allosteric compounds are expected to be highly selective for their target.

 
Abstract: Focal Adhesion Kinase (FAK) is the ke...Read More 

Focal Adhesion Kinase (FAK) is the key integrator of signals transduced by growth and adhesion receptors and thereby transmits crucial signals controlling cell proliferation, survival, adhesion and migration. In cancer FAK is frequently upregulated and is a major driver of tumor growth, invasion and metastasis. Hence FAK is an attractive cancer target and several FAK inhibitors have been tested in the clinic. Most FAK inhibitors developed to date target the ATP binding pocket and due to the high conservation of this site, resulting compounds often display off-target activity and high toxicity. We take an alternative approach, where we in a first stage structurally and functionally characterize native mechanisms regulating FAK activity. In a second phase, we utilize this knowledge for the discovery of allosteric compounds targeting these mechanisms. We take a fragment based drug discovery approach using experimental and computational screening for the discovery of initial fragment compounds binding to surface pockets of FAK. Subsequent structural analysis of bound fragments by X-ray crystallography identifies the binding site and mode and guides the structure-based elaboration of fragments into high-affinity compounds that allosterically modulate FAK activity. Since such regulatory mechanisms are highly divergent among different kinases, compounds targeting these sites are expected to exhibit high specificity and hence low toxicity. In summary, we present a platform for a dual approach where mechanistic insights can guide the development of allosteric inhibitors with ultra-high selectivity.

Benefits:
-Multidisciplinary
-Allosteric targeting
-High selectivity
-Utilise native regulatory mechanisms

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14:55
Performance of Conformal Prediction in Prospective Applications of QSAR and QSPR Models Supporting Drug Discovery
 
Ingo  Mugge
Ingo Mugge
Senior Research Fellow
Alkermes
About Speaker: Dr. Ingo Mügge is a Senior Research Fellow at Alkermes, Inc. In this role he leads the Modeling & Informatics efforts in the Discovery department contributing to the advancement of early drug discovery projects. Dr. Mügge has more than 20 years... Read Full Bio 
 
 
Ingo  Mugge
Ingo Mugge
Senior Research Fellow
Alkermes
 
About Speaker:

Dr. Ingo Mügge is a Senior Research Fellow at Alkermes, Inc. In this role he leads the Modeling & Informatics efforts in the Discovery department contributing to the advancement of early drug discovery projects. Dr. Mügge has more than 20 years of experience working in the pharmaceutical industry in leadership positions at Bayer Healthcare, Boehringer Ingelheim, and Alkermes focusing on research in CNS, immunology, and cardio-metabolic related diseases. His research interests include in silico driven drug design techniques such as virtual screening, structure-based drug design, and predictive modeling. He has published more than 60 scientific papers and book chapters, co-organized scientific conferences, and serves on the scientific advisory board of Molecular Informatics. Dr. Mügge holds a European diploma degree in physics from the Humboldt University Berlin and a doctorate degree in computational chemistry from the Free University Berlin. Postdoctoral appointments allowed him to work with Yvonne Martin at Abbott Laboratories and Arieh Warshel at the University of Southern California.

 
Abstract: Decisions made by drug design teams o...Read More 

Decisions made by drug design teams on synthesizing and advancing compounds for lead optimization are increasingly influenced by in silico predictions of on- and off-target activities as well as physico-chemical and ADME properties of small molecules. Predictive modeling workflows involving multiple endpoints are put in place helping chemists to make early decisions on the fate of design ideas or compound advancement. Therefore, it is of paramount importance to assess quantitatively the confidence in each prediction. In analogy to weather predictions, an intuitive measure of the confidence in a prediction is the percent chance to be correct within a certain activity or property range. To this end, the conformal prediction (CP) formalism was employed providing a well-defined mathematical framework for confidence assessments [1]. It was demonstrated before that CP generates efficient and accurate confidence intervals for self-contained data sets [2]. Here we show how CP performs for quasi-prospective (time-split) and also truly prospective predictions. In addition, we show how public data available from Chembl or PubChem perform in predicting compound properties and ADME parameters for compounds measured in related but not identical assays for end points such as aqueous solubility, volume of distribution, and plasma protein binding. For a series of automatically updating models in comparison to static models frozen in time we show that the conformal prediction approach performs robustly in both cases. The observed deterioration in the predictive power of static models over time [3] leads to larger confidence intervals. While the prediction accuracy is maintained static models become less useful over time because of the increasing confidence intervals. The data suggest that CP provides a practical and robust framework for assessing the predictive power of predictive models for prospective applications.

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14:55
Advanced BRET Approaches for Profiling GPCR Pharmacology
 
Kevin  Pfleger
Kevin Pfleger
Head, Molecular Endocrinology & Pharmacology
Harry Perkins Inst. of Medical Research; Uni. of Western Australia
About Speaker: Kevin Pfleger is a National Health and Medical Research Council (NHMRC) RD Wright Fellow and Chief Scientific Advisor of ASX-listed Dimerix Limited. He was awarded his MA and PhD from Cambridge and Edinburgh Universities respectively, and relocated t... Read Full Bio 
 
 
Kevin  Pfleger
Kevin Pfleger
Head, Molecular Endocrinology & Pharmacology
Harry Perkins Inst. of Medical Research; Uni. of Western Australia
 
About Speaker:

Kevin Pfleger is a National Health and Medical Research Council (NHMRC) RD Wright Fellow and Chief Scientific Advisor of ASX-listed Dimerix Limited. He was awarded his MA and PhD from Cambridge and Edinburgh Universities respectively, and relocated to Australia in 2002. His accolades include NHMRC 10 of the Best Research Projects 2010, Australian Museum Eureka Prize for Emerging Leader in Science 2011, Endocrine Society Early Investigators Award 2012, Endocrine Society of Australia's Mid-Career Research Award 2014, NHMRC Research Excellence Award 2014 for top-ranked fellowship in category and British Pharmacological Society (BPS) Novartis Prize 2016. He is Chair of the Scientific Advisory Committee of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, serves on the International Advisory Group of BPS and is Chair of the Accelerating Australia Executive Committee.

 
Abstract: Profiling in live cells and in real t...Read More 

Profiling in live cells and in real time can provide valuable insights into GPCR pharmacology, including ligand binding, G protein coupling, arrestin recruitment, internalization, trafficking and recycling, as well as interactions with a variety of other regulatory and signalling molecules. Furthermore, the complexity of GPCR signalling systems is magnified by the concepts of biased signalling, allosterism and receptor heteromerization. Bioluminescence resonance energy transfer (BRET) is a technique that can be used to investigate all these aspects of GPCR pharmacology, through real-time monitoring of molecular proximity in live cells. We have been at the forefront of developing these approaches over the last decade, with recent highlights including (1) developing the NanoBRET ligand binding assay enabling real-time, live cell monitoring of ligand-receptor interactions for both small molecules and peptides [1]; (2) further developing the BRET trafficking assay pioneered by Nevin Lambert to enable real-time, live cell monitoring of protein trafficking from the plasma membrane to various subcellular compartments [2]; and (3) most recently publishing the first demonstration of BRET using CRISPR/Cas9 technology to add BRET-tags to endogenous proteins to monitor receptor function [3]. All of these approaches are very powerful and complement the more established receptor-G protein and receptor-arrestin BRET proximity assays that we also utilize. Such comprehensive kinetic profiling of receptor complexes enables improved understanding of ligand bias with and without the added complexity of heteromerization.

1. Stoddart LA, Johnstone EKM, Wheal AJ, Goulding J, Robers MB, Machleidt T, Wood KV, Hill SJ and Pfleger KDG (2015) Application of BRET to monitor ligand binding to GPCRs. Nature Methods 12: 661-663
2. Tiulpakov A, White CW, Abhayawardana RS, See HB, Chan AS, Seeber RM, Heng JI, Dedov I, Pavlos NJ, Pfleger KDG (2016) Mutations of vasopressin receptor 2 including novel L312S have differential effects on trafficking. Molecular Endocrinology 30: 889-904
3. White CW, Vanyai HK, See HB, Johnstone EKM, Pfleger KDG (2017) Using nanoBRET and CRISPR/Cas9 to monitor proximity to a genome-edited protein in real-time. Scientific Reports 7: 3187

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14:55
Leniolisib (CDZ173) - Discovery of a New Generation of Potent and Selective PI3Kdelta Inhibitors for the Treatment of Autoimmune and Inflammatory Diseases
 
Nicolas Soldermann
Nicolas Soldermann
Senior Investigator and Group Leader, Global Discovery Chemistry
Novartis
About Speaker: Nicolas Soldermann studied chemistry at Ecole Nationale Superieure de Chimie de Mulhouse where he obtained his Diplôme d’Ingénieur Chimiste de l’Ecole Nationale Supérieure de Chimie de Mulhouse, France, majoring in medicinal and bioorganic che... Read Full Bio 
 
 
Nicolas Soldermann
Nicolas Soldermann
Senior Investigator and Group Leader, Global Discovery Chemistry
Novartis
 
About Speaker:

Nicolas Soldermann studied chemistry at Ecole Nationale Superieure de Chimie de Mulhouse where he obtained his Diplôme d’Ingénieur Chimiste de l’Ecole Nationale Supérieure de Chimie de Mulhouse, France, majoring in medicinal and bioorganic chemistry and a Master in Sciences in organic and macromolecular synthesis from the University of Haute-Alsace, France. He then moved in 1998 to Switzerland to the University of Neuchâtel for a PhD in organic chemistry with Prof. R. Neier. In 2002, he moved to Stanford University in the US for a Postdoc with Prof. P.A. Wender. Nicolas joined Novartis in 2003 in the Global Discovery Chemistry department as an investigator in medicinal chemistry and since then worked in Hit-to-Lead and Lead Optimization project for several diseases areas such as neurosciences, autoimmunity & transplantation and oncology. He led several projects from exploratory to late stage lead optimization yielding several clinical compounds including leniolisib currently in phase 2 for APDS. Nicolas spent about 10 years in the autoimmune and Transplantation field and since 2015 he is a Senior Investigator/Group Leader in Oncology and Immuno-Oncology.

 
Abstract: The discovery and characterization of...Read More 

The discovery and characterization of leniolisib (CDZ173), a potent and selective inhibitor of Phosphoinositide3-kinase delta (PI3Kdelta) will be presented. We report how innovative medicinal chemistry efforts led to the identification of a novel and promising tetrahydro-pyrido-pyrimidine lead series that could be rapidly further optimized into a favorable physicochemical space and resulted in the identification of leniolisib, currently in clinical development as an anti-inflammatory therapeutic agent.

In vitro, leniolisib shows the capacity to inhibit a large spectrum of immune cell functions. In vivo, leniolisib inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. In preclinical animal models, leniolisib potently inhibited the antibody production in response to immunization and reduced clinical symptoms in rat collagen-induced arthritis models. Structurally, leniolisib differs significantly from the first generation of PI3Kdelta and/or PI3Kgamma/delta-selective clinical compounds and, therefore, could differentiate favorably in its safety profile.

Leniolisib is currently in clinical trial in patients suffering from APDS/PASLI, a disease caused by gain-of-function mutation of PI3Kdelta.

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15:20
Exploring Protein-Ligand Binding Using Three-Dimensional Pharmacophore Patterns
 
Gerhard  Wolber
Gerhard Wolber
Professor
Freie Universität Berlin
About Speaker: Prof. Dr. Gerhard Wolber is professor for Pharmaceutical Chemistry and head of the molecular design lab at the Institute of Pharmacy at the Freie Universitaet Berlin. After his studies of pharmacy at the University of Innsbruck and Computer Science a... Read Full Bio 
 
 
Gerhard  Wolber
Gerhard Wolber
Professor
Freie Universität Berlin
 
About Speaker:

Prof. Dr. Gerhard Wolber is professor for Pharmaceutical Chemistry and head of the molecular design lab at the Institute of Pharmacy at the Freie Universitaet Berlin. After his studies of pharmacy at the University of Innsbruck and Computer Science at the Technical University of Vienna, he received his PhD in pharmaceutical chemistry at the University of Innsbruck. In 2003 he co-founded the company Inte:Ligand together with partners from the University of Innsbruck, Austria. In 2008 he changed back to academia as assistant professor and group head of the Computer-Aided drug design group at the University of Innsbruck before changing to the Freie Universitaet Berlin in 2010. His research focuses on computational drug design and the development of drug development and virtual screening tools.

 
Abstract: 3D pharmacophores have become an esta...Read More 

3D pharmacophores have become an established and consolidated method for in-silico drug discovery – mainly due to their ability to reflect the way of thinking of medicinal chemists in terms of hit identification, hit expansion and lead optimization. The simplicity and descriptive character of such a 3D pharmacophore model thus enables clear communication and rapid feedback cycles between modeling and synthesis teams. Despite the broad usage of the methodology, there are still several pitfalls and challenges for successful pharmacophore modeling – mainly related to the algorithmic challenge of flexibly fitting a molecule to a 3D pharmacophore model in a computationally efficient way. In this talk, structure- and ligand-based 3D pharmacophore application studies will be presented and critically discussed in the context of virtual screening algorithms and overlay algorithms.

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15:20
The Inner Workings of a GPCR: Signalling-Specific Conformations of Vasopressin V2 Receptor
 
Dmitry  Veprintsev
Dmitry Veprintsev
Professor of Molecular and Cellular Pharmacology, Centre for Membrane Proteins and Receptors
University of Nottingham
About Speaker: Dmitry is Professor of Molecular and Cellular Pharmacology in the School of Life Sciences, University of Nottingham. Dmitry did his PhD in biophysics and protein folding at the Russian Academy of Sciences and at the Ohio State University, USA. In 199... Read Full Bio 
 
 
Dmitry  Veprintsev
Dmitry Veprintsev
Professor of Molecular and Cellular Pharmacology, Centre for Membrane Proteins and Receptors
University of Nottingham
 
About Speaker:

Dmitry is Professor of Molecular and Cellular Pharmacology in the School of Life Sciences, University of Nottingham. Dmitry did his PhD in biophysics and protein folding at the Russian Academy of Sciences and at the Ohio State University, USA. In 1999, he joined Sir Alan Fersht at the MRC Centre for Protein Engineering and later at the MRC Laboratory of Molecular Biology in Cambridge, UK, first as a Human Frontier postdoctoral fellow and later as a staff scientist. There he focused on the structural and biophysical characterisation of the tumour suppressor p53 and on the development of chemical chaperone strategy to rescue destabilised cancer-associated mutants of p53. In 2010 he became a group leader at the Paul Scherrer Institute in Switzerland where focused his research on the role of protein dynamics in signalling by G protein coupled receptors. He moved to Nottingham in the Autumn 2017.

G protein-coupled receptors (GPCRs), the largest human membrane receptor family, translate extracellular signals, such as changes in the concentrations of hormones and neurotransmitters, into physiological responses by activating one or several intracellular signalling pathways mediated by multiple G proteins and arrestins. His laboratory is interested in structure and dynamics of receptors and their effector molecules and the role of conformations in modulation of signalling. The second focus of his laboratory is on the dynamics of interconnected signalling networks. To link the dynamic behaviour of receptors and effectors with the dynamics of the signalling response, his group aims to develop a proof-of-principle model of cellular signalling by combining experimental and modelling results to characterise the cellular signalling pathways associated with the activation of G protein-coupled receptors. A better understanding of cellular signalling networks will lead to the development of new drugs with reduced side effects, identification of novel drug targets in the signalling networks and development of personalised medicine through deep-signalling pharmacology.

 
Abstract: The physiological effects of G protei...Read More 

The physiological effects of G protein-coupled receptor activation depend on their ability to activate effector proteins, primarily G proteins and β-arrestins. In many cases, beneficial and detrimental pharmacological effects are mediated by different effectors. Here we determined the function of each individual amino acid of vasopressin V2 receptor in signalling through several G protein subtypes and β-arrestins. We identified residues involved in common and effector-specific allosteric connections of ligand and effector binding sites. We show how changes in the ligand binding pocket bias the receptor towards specific signalling pathways. Our data suggest the existence of signalling-specific micro-conformations, which are unique for each activated effector. These microstates explain the molecular basis for functional selectivity and biased signalling by G protein-coupled receptors and outline the path to rational engineering of biased therapeutics.

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15:20
Investigating the Nature of Cryptic Pocket Formation Through Enhanced Sampling Simulations
 
Francesco  Gervasio
Francesco Gervasio
Professor
University College London
About Speaker: Francesco Luigi Gervasio holds a Chair of biomolecular modelling at University College London where he is Graduate Tutor, professor of Chemistry and professor of Structural and Molecular Biology. He holds a Ph.D. degree in chemistry from the Universi... Read Full Bio 
 
 
Francesco  Gervasio
Francesco Gervasio
Professor
University College London
 
About Speaker:

Francesco Luigi Gervasio holds a Chair of biomolecular modelling at University College London where he is Graduate Tutor, professor of Chemistry and professor of Structural and Molecular Biology. He holds a Ph.D. degree in chemistry from the University of Firenze and has been a Postdoc in the group of Michele Parrinello from 2002 to 2006, before becoming Assistant Professor at ETH Zurich and then joining the Spanish National Cancer Research Centre as the leader of the computational biophysics group (2009−2013). He is at UCL as full professor since 2013. He is a member of the Faculty of 1000 and an editor of various journals, including Nature group's Scientific Reports. His research focuses on the development of computer simulations methods and their integration with NMR spectroscopy to understand in details the dynamics of biomolecular systems, with a focus in the activation dynamics of oncogenic kinases.

 
Abstract:  “Cryptic” pockets, ...Read More 

 “Cryptic” pockets, that is, sites on protein targets that only become apparent when a drug bind, offer an attractive opportunity for the development of allosteric drugs for difficult targets. However, due to their “hidden” nature, they have been in most cases discovered serendipitously. What is more, the molecular mechanism by which cryptic sites are formed is not clear. We used a number of enhanced-sampling simulation approaches [1] with different state-of-the-art force-fields to investigate the nature of cryptic sites in various pharmacologically relevant targets. The mechanisms of cryptic site formation that we observe is suggestive of an interplay between induced-fit and conformational selection. Employing this insight, we developed a novel approach “SWISH” (Sampling Water Interfaces through Scaled Hamiltonians) [2] and used it in combination with Metadynamics to understand the binding mode of a novel allosteric modulator of the extracellular portion of the Fibroblast Growth Factor Receptor [3].

1. A. Cavalli, A. Spitaleri, G. Saladino & F.L. Gervasio Acc. Chem. Res., 48, 277, 2015
2. V.Oleinikovas, G. Saladino, B.P. Cossins & F. L. Gervasio J. Am. Chem. Soc. 138, 14257, 2016
3. C. Herbert, et al. Cancer Cell, 23, 489, 2013

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15:45
Towards the Next Generation of FEP Calculations in Lead Compound Optimization
 
Thomas Steinbrecher
Thomas Steinbrecher
Regional Manager, Application Science
Schrödinger
About Speaker: Thomas Steinbrecher studied Chemistry at the University of Freiburg in Germany and earned a diploma with distinction in Physical Chemistry. He completed a Ph.D. thesis on “Computer Simulations of Protein-Ligand Interactions” in 2005. He joined th... Read Full Bio 
 
 
Thomas Steinbrecher
Thomas Steinbrecher
Regional Manager, Application Science
Schrödinger
 
About Speaker:

Thomas Steinbrecher studied Chemistry at the University of Freiburg in Germany and earned a diploma with distinction in Physical Chemistry. He completed a Ph.D. thesis on “Computer Simulations of Protein-Ligand Interactions” in 2005. He joined the developer team of the Amber MD package as a Postdoc at the Scripps Research Institute in San Diego and Rutgers University in New Jersey. The work focus was on efficient free energy calculation methods and QM/MM simulations of charge transfer. After returning to Germany in 2008, Thomas established a junior research group at the Karlsruhe Institute of Technology, working on fast electron transfer phenomena in DNA and proteins. He joined Schrodinger in 2013 where he is responsible for the large scale application of free energy calculation methods in pharmaceutical drug design. He currently is responsible for the European Applications Science Department.

 
Abstract: The accurate prediction of protein&mi...Read More 

The accurate prediction of protein−ligand binding affinities, famously described as the holy grail of molecular modelling, represents an extraordinarily challenging task, but also a potential high-value application of computer-aided drug design in the pharmaceutical industry.

Free energy perturbation (FEP) calculations using molecular dynamics simulation (MD) sampling is by far the most widely employed approach to achieve accurate binding free energy predictions. The FEP+ methodology is based on a rigorous statistical mechanics framework, a robust, physics-based representation of the system energetics, and explicit treatment of the important degrees of freedom in the system, including explicit water molecules and full ligand and receptor flexibility. We have in the past reported on many advances in free energy methods, among them employing enhanced sampling methods, building state-of-the-art force fields, and automatic generation of molecule transformation networks.

In this talk, we outline recent advances towards next-generation FEP+ applications, both for increasing simulation throughput as well as broadening the technology’s domain of applicability. The focus will be on current hot topics in pharmaceutical research, such as applying FEP+ calculations to macrocycles, covalent inhibitors or scaffold core-hopping. Together with the continuing vast increase in computational resources due to GPU and cloud computing, this progress has made FEP+ a viable and robust technology to drive hit-to-lead and lead optimization, allowing for the exploration of chemical space in silico with unprecedented accuracy.

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15:45
Dynamics of Receptor Activation Studied in Real Time by FRET-Based
 
Carsten  Hoffman
Carsten Hoffman
Director, Institute of Molecular Cell Biology
University Hospital Jena
About Speaker: With more than 20 years of experience in GPCR pharmacology and specialized expertise in fluorescence resonance energy transfer approaches (FRET), Prof. Hoffmann´s group is one of the leading academic groups in the development of novel FRET-based sen... Read Full Bio 
 
 
Carsten  Hoffman
Carsten Hoffman
Director, Institute of Molecular Cell Biology
University Hospital Jena
 
About Speaker:

With more than 20 years of experience in GPCR pharmacology and specialized expertise in fluorescence resonance energy transfer approaches (FRET), Prof. Hoffmann´s group is one of the leading academic groups in the development of novel FRET-based sensors for real-time kinetic analyses for GPCR conformational changes in living cells. Since April 2017 Prof. Dr. Carsten Hoffmann is the newly appointed director of the institute for molecular cell biology at the university hospital Jena.

 
Abstract: The recently published crystal struct...Read More 

The recently published crystal structures of the adenosine A1 and A2A receptor in the inactive state and A2A receptor in the active state revealed static endpoints of the conformational changes associated with the activation process. To investigate the activation dynamics of different adenosine receptor subtypes we used fluorescence resonance energy transfer (FRET) measurements of a modified A1 and A2A receptor construct (A1R, A2AR). Those optical probes where designed by insertion of the fluorescein arsenical hairpin binder (FlAsH) motif into the 3rd intracellular loop and fusion of the cyan fluorescent protein (CFP) to the C-terminus of the receptor. Amino acids identified within the ligand binding pocket, as revealed from the crystal structure, were individually mutated and hence, we created 10 different biosensors for each receptor. To compare A1R and A2AR dynamics, we established HEK293 cell lines stably expressing these optical probes and investigated the signal amplitude and the receptor activation kinetics in living cells. We identified three different effects of these mutations. One class causes problems in membrane localization of the A1 but not the A2A receptor. The 2nd group is involved in binding of the ribose moiety and has stronger effects in the A1 compared to the A2A receptor. The 3rd class consists of the mutants that are involved in binding of the adenine moiety and have similar effects for adenosine and theophylline binding for the A2A receptor. Thus, our study provides evidence that similar amino acids serve different functions within the A1 and A2A receptor ligand binding pocket. In summary the different signal amplitudes and different activation kinetics are indicative for a different activation behavior of the A1 and A2A receptor and give new insight into A1 receptor activation.

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15:45
Uncoupling mTORC2 from AGC Kinases to Modulate Tumour Growth
 
Angus  Cameron
Angus Cameron
Principal Investigator, Tumour Biology
Barts Cancer Institute
About Speaker: I completed my PhD at the University of Glasgow working on immune receptor signal transduction before moving to CRUK London Research Institute to work with Professor Peter Parker on protein kinase C. In 2013 I moved to Barts Cancer Institute to set u... Read Full Bio 
 
 
Angus  Cameron
Angus Cameron
Principal Investigator, Tumour Biology
Barts Cancer Institute
 
About Speaker:

I completed my PhD at the University of Glasgow working on immune receptor signal transduction before moving to CRUK London Research Institute to work with Professor Peter Parker on protein kinase C. In 2013 I moved to Barts Cancer Institute to set up my own group, where my interests focus on protein kinase N and mTOR signalling.

 
Abstract: The master regulator of growth and me...Read More 

The master regulator of growth and metabolism, mTOR, resides in two distinct multiprotein complexes, mTORC1 and mTORC2. The mTORC1 complex can be targeted pharmacologically with rapalogues. Alternatively, both complexes can be inhibited with ATP pocket directed mTOR kinase inhibitors. The use of these inhibitor strategies to treat cancer has shown promise but feedback pathway activation and dose limiting toxicities remain significant problems. Currently there are no pharmacological agents to assess whether mTORC2 specific targeting would offer greater therapeutic benefit. We have developed a dominant negative system for specifically disrupting mTORC2 from recruiting its downstream AGC family targets. Using this system, we demonstrate that uncoupling the mTORC2 pathway is sufficient to suppress tumour growth in xenografts. This work adds to the body of evidence that mTORC2 specific drugs may be useful anti-cancer agents.

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16:10
Afternoon Networking Break
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Drug Design & Medicinal Chemistry
Novel Computational Methods & Predictive Models (cont.)
Moderator: Thomas Steinbrecher, Schrödinger
16:40
Protein Dynamics and Drug Discovery: New Activators of the Hsp90 Chaperone as Anticancer Molecules
 
Giorgio  Colombo
Giorgio Colombo
Principal Investigator
Istituto di Chimica del Riconoscimento Molecolare, CNR
About Speaker: Giorgio Colombo (born 24th June 1971) received his M.Sc. Degree in chemistry in the academic year 1994/1995 from the University of Milano, Final Grade 110/110. After that, he continued his studies obtaining a Ph.D. in chemical sciences from the Unive... Read Full Bio 
 
 
Giorgio  Colombo
Giorgio Colombo
Principal Investigator
Istituto di Chimica del Riconoscimento Molecolare, CNR
 
About Speaker:

Giorgio Colombo (born 24th June 1971) received his M.Sc. Degree in chemistry in the academic year 1994/1995 from the University of Milano, Final Grade 110/110. After that, he continued his studies obtaining a Ph.D. in chemical sciences from the University of Milano in 2000. During the Ph.D period he spent one year as a visiting scientist in the laboratory of Prof. Ken Merz at the Pennsylvania State University, working on computational and theoretical approaches to study enzymatic and protein properties. He then moved to the University of Groningen as a postdoctoral fellow to work on the molecular dynamics simulations of the folding and stability of proteins and peptides. Dr. Giorgio Colombo joined the Institute for Molecular Recognition Chemistry, Italian National Research Council, in 2001 where he is currently head of the biocomputing group. In 2017, he has been appointed as a Full Professor of Organic Chemistry at the University of Pavia. He is author or coauthor of more than 150 scientific publications, all on international journals.

 
Abstract: Hsp90 is a molecular chaperone of piv...Read More 

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through the computational design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Å from the active site.

Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules’ effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary.

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GPCR Targeted Screening
GPCR Signaling Pathways and Mechanisms (cont.)
Moderator: Christoph Klenk, University of Zurich
16:40
The 5-HT6 Receptor-Associated Signalling Network as a Target for the Treatment and Prevention of Cognitive Deficits in Psychiatric Disorders
 
Philippe  Marin
Philippe Marin
Research Director
CNRS
About Speaker: Philippe Marin completed his PhD in Neuropharmacology in 1992 at the University Pierre and Marie Curie (Paris). He got a permanent position at the CNRS in 1993 to study the mechanisms controlling protein translation in neurons and their role in neuro... Read Full Bio 
 
 
Philippe  Marin
Philippe Marin
Research Director
CNRS
 
About Speaker:

Philippe Marin completed his PhD in Neuropharmacology in 1992 at the University Pierre and Marie Curie (Paris). He got a permanent position at the CNRS in 1993 to study the mechanisms controlling protein translation in neurons and their role in neurotoxicity at the Laboratory of Neuropharmacology located in Collège de France (Paris). He joined the Institute of Functional Genomics of Montpellier in 1999, where he is the leader of the “Neuroproteomics and Signalling of Neurological and Psychiatric Disorders” team and of the proteomics platform. This team investigates the signalling mechanisms engaged by various serotonergic receptors and their role in the regulation of mood, cognition, pain transmission and neuronal survival, using state-of-the-art proteomics and phosphoproteomics approaches combined with cell biology, electrophysiology and behavioural studies. The team also participates in projects dedicated to biomarker discovery in neurological disorders, including multiple sclerosis and Alzheimer’s disease, thanks to proteomics strategies. P. Marin is the author of 104 publications and two patents (h index = 39).

 
Abstract: The serotonin (5-HT)6 receptor is a G...Read More 

The serotonin (5-HT)6 receptor is a Gs protein-coupled receptor expressed at early stages of brain development which controls key neuro-developmental processes, including neuronal migration and differentiation. It is emerging as a promising target for the treatment of cognitive deficits observed in neuro-developmental psychiatric disorders such as schizophrenia. However, the signalling mechanisms underlying its control of neural development and cognition remained largely unknown, an issue we addressed using complementary affinity purification coupled to mass spectrometry (AP-MS) proteomics strategies to identify 5-HT6 receptor interacting proteins. These studies revealed that 5-HT6 receptors physically interact with several proteins of the mTOR pathway, including mTOR itself. Further experiments showed that a sustained, 5-HT6 receptor-dependent, activation of mTOR in prefrontal cortex underlies cognitive deficits in two rodent developmental models of schizophrenia, neonatal treatment with the NMDA receptor antagonist phencyclidine (PCP) and rearing in isolation after the weaning. Furthermore, early blockade of the 5-HT6/mTOR pathway during adolescence abolished the overactivation of prefrontal cortical mTOR at the adult stage, rescued the deficit in novel object discrimination and compensated the associated alteration of GABAergic transmission in prefrontal cortex of mice treated neonatally with PCP. Likewise, early administration of a 5-HT6 receptor antagonist or a mTOR inhibitor at a critical stage of adolescence prevented the sustained mTOR activation and the emergence of the associated alterations of cognitive functions and synaptic transmission at adulthood in a mouse model of cannabis abuse during adolescence. Collectively, these findings highlight the potential of AP-MS proteomics strategies to identify novel signalling pathways underlying the pathophysiological effects of G protein-coupled receptors. They suggest that 5-HT6 receptor antagonists, currently in clinical trials as symptomatic treatments of cognitive symptoms in a wide range of CNS disorders, may be repositioned as disease modifiers to alter the course of schizophrenia and prevent the emergence of cognitive deficits at adulthood in at-risk individuals. Such a disease modifying strategy may also be envisaged in young cannabis abusers who show an increased risk of developing later in life psychotic-like symptoms and cognitive deficits reminiscent to those observed in schizophrenia.

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Kinase Inhibitors in Drug Discovery
Optimizing Target Residence Times in Kinase Drug Development
Moderator: Henrik Moebitz, Novartis
16:40
Target Residence-Guided Optimization of Kinase Inhibitors
 
Guido  Zaman
Guido Zaman
Managing Director & Head of Biology
Netherlands Translational Research Center
About Speaker: Guido Zaman is Managing Director and Head of Biology of NTRC, a biotech company based in the Netherlands. NTRC (Netherlands Translational Research Center B.V.) translates novel biological concepts into new small molecule drug leads. Guido Zaman found... Read Full Bio 
 
 
Guido  Zaman
Guido Zaman
Managing Director & Head of Biology
Netherlands Translational Research Center
 
About Speaker:

Guido Zaman is Managing Director and Head of Biology of NTRC, a biotech company based in the Netherlands. NTRC (Netherlands Translational Research Center B.V.) translates novel biological concepts into new small molecule drug leads. Guido Zaman founded NTRC together with former colleagues at Merck, Sharp & Dohme (MSD) in 2011. Guido Zaman received his Ph.D. in Science from the University of Nijmegen and worked for five years at the Netherlands Cancer Institute in Amsterdam, before he moved to pharmaceutical industry in 1996. At N.V. Organon, Schering-Plough and MSD he led several multidisciplinary and international teams, including on protein kinases, and was senior director of Molecular Pharmacology.

 
Abstract: Target residence time is thought to b...Read More 

Target residence time is thought to be a more important determinant of the biological activity of kinase inhibitors than their potency (IC50) in enzyme assays or their binding affinity (KD) measured at equilibrium. We studied NTRC 0066-0, a selective inhibitor of the spindle assembly checkpoint kinase TTK, which was developed at NTRC, together with eleven TTK inhibitors from different chemical classes developed by others. Parallel testing showed that the cellular activity of the TTK inhibitors correlates with their binding affinity and, more strongly, with target residence time. X-ray structures revealed that the most potent inhibitors induce a unique structural conformation. Based on this insight, new TTK inhibitors were developed with longer target residence times and very potent anti-proliferative activity. Benefits: – Target residence time in lead optimization – Structure-based drug discovery – Relationship between binding kinetics and cellular activity – Identification of new and effective therapeutics

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17:05
Getting the Most out of Protein Structures: Structure-Based Molecular Design in the Big Data Era
 
Matthias  Rarey
Matthias Rarey
Professor, ZBH Center for Bioinformatics
Universität Hamburg
About Speaker: Prof. Dr. Matthias Rarey heads the Center for Bioinformatics at the University of Hamburg, Germany.His background is in Computer Science (M.Sc. Paderborn, 1992, Ph.D. Bonn, 1996) with a focus on Bio- and Cheminformatics. Until July 2002, he was group... Read Full Bio 
 
 
Matthias  Rarey
Matthias Rarey
Professor, ZBH Center for Bioinformatics
Universität Hamburg
 
About Speaker:

Prof. Dr. Matthias Rarey heads the Center for Bioinformatics at the University of Hamburg, Germany.His background is in Computer Science (M.Sc. Paderborn, 1992, Ph.D. Bonn, 1996) with a focus on Bio- and Cheminformatics. Until July 2002, he was group leader for Cheminformatics at the Fraunhofer Institute for Algorithms and Scientific Computing (SCAI, former part of GMD). In 1997 and 2000, Prof. Rarey performed research in the cheminformatics departments of SmithKline Beecham (King of Prussia, PA) and Roche Bioscience (Palo Alto, CA). Prof. Rarey is a co-founder of the cheminformatics company BioSolveIT GmbH located in Sankt Augustin. Since 2002, he heads the Center for Bioinformatics at the University of Hamburg. He is the director of the Research Group for Computational Molecular Design which focuses on the development of new algorithms for problems occurring in molecular design, innovative approaches to cheminformatics and new molecular visualization techniques. Since 1993, Prof. Dr. Matthias Rarey has been developing innovative Software tools for structure- and ligand-based molecular design, several of which have gained international recognition, e.g. FlexX, Features Trees, PoseView, SMARTSeditor, Mona, ProToss and HYDE.

Since 2014, Prof. Rarey is an Associate Editor of the Journal of Chemical Information and Modeling of the American Chemical Society. Furthermore, he is a member in the scientific committees of Wire Computational Molecular Science and the Journal of Molecular Graphics and Modelling as well as several national and international conferences program committees. He is the spokesman of the Fachgruppe Bioinformatik (FaBI), a joint working group founded in 2014 by the Gesellschaft für Informatik e.V., the Dechema e.V., the Gesellschaft für Biochemie und Molekularchemie and the Gesellschaft Deutscher Chemiker (GDCh).

Together with his colleagues, Prof. Rarey established the study programs M.Sc. Bioinformatik and B.Sc. Computing in Science and is a member of their examinations boards as well as the responsible for the study program M.Sc. Bioinformatik. Prof. Rarey is a member of the faculty council of the Faculty of Mathematics, Informatics and Natural Sciences, he heads the PhD committee of the Faculty of Informatics. He is a liaison professor for the Studienstiftung des deutschen Volkes.

 
Abstract: With the availability of more and mor...Read More 

With the availability of more and more protein structures, structure-based design became a key technology within the early phases of drug design. Protein structures are the only mean by which a truly rational design approach get in sight. While modeling techniques like docking and scoring dealing with small series of protein structures are well established, our methodologies to explore the wealth of information hidden in large collections of protein structures are still rather limited. Most search engines on protein structures are based on text rather than on structural elements and the analysis of protein structure still requires labor-intense manual steps.

In this talk, new technologies will be presented addressing this opportunity to learn from large structure collections [1,2]. On the one hand, the automation of structure preprocessing in the context of drug design play a crucial role in exploiting large amount of structural data. On the other hand, search methods allowing to perform geometric queries to structures enable knowledge-driven design decisions. Several examples ranging from interaction geometry analysis, molecular flexibility analysis to design by analogy will be presented.

[1] Fährrolfes, R.; Bietz, S.; Flachsenberg, F.; Meyder, A.; Nittinger, E.; Otto, T.; Volkamer, A.; Rarey, M. (2017). ProteinsPlus: a web portal for structure analysis of macromolecules. Nucleic Acids Research, 45:W337-W343.
[2] Bietz, S.; Inhester, T.; Lauck, F.; Sommer, K.; von Behren, M.; Fährrolfes, R.; Flachsenberg, F.; Meyder, A.; Nittinger, E.; Otto, T.; Hilbig, M.; Schomburg, K.; Volkamer, A.; Rarey, M. (2017). From cheminformatics to structure-based design: Web services and desktop applications based on the NAOMI library. Journal of Biotechnology:in press.

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17:05
Deciphering Complexity of GPCR Signaling by Real Time Optophysiology
 
Kirill  Martemyanov
Kirill Martemyanov
Professor, Neuroscience
The Scripps Research Institute
About Speaker: Dr. Martemyanov’s laboratory studies fundamental aspects of neurotransmitter signaling in the nervous system. Over the years his laboratory uncovered and characterized many novel signaling molecules involved in neurotransmission involved in vision,... Read Full Bio 
 
 
Kirill  Martemyanov
Kirill Martemyanov
Professor, Neuroscience
The Scripps Research Institute
 
About Speaker:

Dr. Martemyanov’s laboratory studies fundamental aspects of neurotransmitter signaling in the nervous system. Over the years his laboratory uncovered and characterized many novel signaling molecules involved in neurotransmission involved in vision, motor control, cognition and actions of addictive drugs. Dr. Martemyanov received his PhD degree in 2000 from the Russian Academy of Sciences. Upon completion of the postdoctoral training at the Harvard Medical School, he joined faculty at the Pharmacology Department at University of Minnesota as a tenure-track Assistant Professor. His laboratory moved to the Scripps Research Institute on Jupiter, FL campus where he became tenured Associate Professor in 2011 and in 2016 was promoted to the rank of Full Professor. Dr. Martemyanov published close to 100 research papers on various aspects of cellular signaling and neuronal communication and his research received many accolades including McKnight Land-Grant Professorship in 2008, Independent Scientist Award from National Institute on Drug Abuse in 2009 and prestigious Cogan Award from the Association for Research in Vision and Ophthalmology in 2014. He directs a productive research group and is well funded for the investigation of the neuronal signaling mechanisms by the National Institutes of Health.

 
Abstract: Activation of G protein coupled recep...Read More 

Activation of G protein coupled receptors (GPCRs) exerts an enormous diversity of physiological effects on cells. In the nervous system setting, they are responsible for the action of the vast number of neuromodulators each characterized by unique properties. How GPCRs encode such complexity of signals is poorly understood. To enable deciphering signaling logic of GPCRs, we have developed approaches where we study GPCR action by real time optical recordings.

Our first platform monitors the ability of GPCR to activate each of the 14 Ga subunits by following kinetics of rearrangement in heterotrimers with Bioluminescent Resonance Energy Transfer (BRET) in reconstituted HEK293 cells. Using this approach we documented unique profiles of Ga subunit engagement by GPCRs that form characteristic “fingerprints” believed to define specificity of GPCR actions in cells. We further demonstrated how these GPCR-G protein activation profiles are affected by GPCR drugs and disease mutations.

Our second approach aims to resolve the complexity of GPCR signaling in the endogenous neuronal circuits. For this we developed a novel conditional reporter mouse that permits analyzing actions of a variety of GPCRs by monitoring their effects on cAMP kinetics in real time. We combined this approach with cell-specific manipulations, CRISPR/Cas9 editing and optogenetic stimulation to dissect complexity of GPCR signal integration during computation of reward signals in the native neurons. The results obtained by these approaches revealed novel insights into GPCR biology and pharmacology.

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17:05
Binding Kinetics Survey of the Drugged Kinome
 
Amaury  Fernández-Montalván
Amaury Fernández-Montalván
Senior Scientist, Lead Discovery Berlin
Bayer AG
About Speaker: Amaury Fernández-Montalván is a Senior Research Scientist and Laboratory Head at Bayer Drug Discovery in Berlin. He studied Biochemistry in the University of Havana and obtained his PhD from the Technical University of Munich. Thereafter, he was a ... Read Full Bio 
 
 
Amaury  Fernández-Montalván
Amaury Fernández-Montalván
Senior Scientist, Lead Discovery Berlin
Bayer AG
 
About Speaker:

Amaury Fernández-Montalván is a Senior Research Scientist and Laboratory Head at Bayer Drug Discovery in Berlin. He studied Biochemistry in the University of Havana and obtained his PhD from the Technical University of Munich. Thereafter, he was a postdoctoral researcher at the Novartis Institutes of Biomedical Research in Basel, and Merck Serono International S.A in Geneva. His current responsibilities with Bayer include developing and performing biochemical and biophysical assays for compound identification and profiling in screening, hit-to-lead, and lead optimization campaigns.

 
Abstract: In recent years binding kinetics has ...Read More 

In recent years binding kinetics has enjoyed increasing acceptance as optimization parameter in target-based drug discovery. The underlying idea proposes that compound’s association (kon) and dissociation (koff) rates for primary- and off-targets are better predictors for efficacy and safety than steady-state affinity per se (KD = koff / kon). While appealing, this concept is mainly backed by studies performed with small and/or incomplete drug-target interaction datasets.

Here we present a comprehensive analysis of the binding kinetic and affinity parameters of 270 small-molecule kinase inhibitors against 40 clinically relevant kinases.

Surprisingly, for the wide spectrum of kinase-inhibitors profiled, our results reveal that affinity is mainly driven by on-rates. On the other hand, the proportion of slow off-rate interactions increases as compounds progress through clinical development phases, whereas the same does not apply for fast on-rates. We assess if target selectivity can be differently assessed from the equilibrium- or kinetic perspectives. Furthermore, we identify cases in which binding kinetics parameters could be effectively used to model the dynamics of target occupancy in vivo. Finally, we disclose structure-kinetic relationships which add to the existing structure-activity relationship knowledge and provide a rational basis for the prospective design of kinetic rate constants.

Our results will contribute to realize the potential of binding kinetics for drug discovery and represent a valuable resource for future studies in this field.

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17:30
Structure-Based Computational Methods for Kinase-Centric Drug Development
 
Andrea  Volkamer
Andrea Volkamer
Assistant Professor, Physiology
Charité Universitätsmedizin Berlin
About Speaker: Andrea Volkamer received her Master degree in Bioinformatics from Saarland University in 2007. After a one year research stay at Purdue University (USA), she joint the group of Prof. Dr. M. Rarey at the ZBH, Hamburg. In 2013, she defended her PhD the... Read Full Bio 
 
 
Andrea  Volkamer
Andrea Volkamer
Assistant Professor, Physiology
Charité Universitätsmedizin Berlin
 
About Speaker:

Andrea Volkamer received her Master degree in Bioinformatics from Saarland University in 2007. After a one year research stay at Purdue University (USA), she joint the group of Prof. Dr. M. Rarey at the ZBH, Hamburg. In 2013, she defended her PhD thesis with focus on computational active site and druggability predictions. After a short ProExzellezia PostDoc period, she joint BioMedX Innovation Center in Heidelberg as a PostDoc researcher, where she has been working on tools to assist the development of selective kinase inhibitors. Since July 2016, Andrea Volkamer has been an assistant professor at the Charité Berlin with the focus on structural bioinformatics and in-silico toxicicology predictions.

 
Abstract: Protein kinases are involved in a var...Read More 

Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. The focus of pharmaceutical research on this enzyme class resulted in roughly 34 FDA approved small molecules. Nevertheless, only a small number of kinases are established therapeutic key targets and most kinase inhibitors are unintentionally promiscuous [1].

Over the last years, several computational methods have been developed to address these shortcomings in kinase-centric drug development. An extract of such will be showcased here. First, using the wealth of available kinase structures, a computational druggability assessment of the entire human kinome will be presented which allows prioritizing (yet) untapped kinases for drug discovery efforts [2]. Second, a novel structure-based approach to tackle compound selectivity deficits will be introduced [3]. The method allows identifying specificity-determining subpockets between closely related kinases, i.e., key- and off-targets, solely based on their three-dimensional structures. Finally, current attempts for structure-based off-target identification will be discussed.

The methods incorporate the wealth of available structural information and can be applied (I) to prioritize novel kinases as drug targets, (II) to detect similarities and dissimilarities between hundreds of structures at once as well as (III) to identify potential off-targets, and, thus, can facilitate the design of more selective compounds.

References:
[1] Kooistra A., Volkamer A., “Kinase-Centric Computational Drug Development”, in Annual Reports in Medicinal Chemistry, Vol. 50, ed. Goodnow R., Elsevier, 2017, 153-192, in press
[2] Volkamer A., Eid S., Turk S., Jaeger S., Rippmann F., Fulle S., ”Pocketome of human kinases: Prioritizing the ATP binding sites of (yet) untapped protein kinases for drug discovery”. JCIM, 2015, 55(3):538-49
[3] Volkamer A., Eid S., Turk S., Rippmann F., Fulle S., “Identification and Visualization of Kinase-Specific Subpockets”, JCIM, 2016, 56(2):335-46

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17:30
G Proteins: Inhibitor SAR and GPCRdb Data & Tools
 
David  Gloriam
David Gloriam
Associate Professor, Drug Design and Pharmacology
University of Copenhagen
About Speaker: David E. Gloriam got his PhD from Uppsala University and after two postdocs at EMBL-EBI and GSK moved to the University of Copenhagen in 2008 where he leads a group for computational drug design. In 2013, he took over the stewardship of the community... Read Full Bio 
 
 
David  Gloriam
David Gloriam
Associate Professor, Drug Design and Pharmacology
University of Copenhagen
 
About Speaker:

David E. Gloriam got his PhD from Uppsala University and after two postdocs at EMBL-EBI and GSK moved to the University of Copenhagen in 2008 where he leads a group for computational drug design. In 2013, he took over the stewardship of the community-driven GPCR database, GPCRdb, expanding the services with e.g. reference data and tools for mutagenesis and crystallisation experiments. In 2014, he received both a ERC Starting Grant and a Lundbeck Foundation Fellowship to identify physiological and tool ligands to characterise orphan receptors. His lab is currently setting up receptor crystallography and a biased agonist resource.

 
Abstract: G proteins are key mediators of G pro...Read More 

G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. We recently reported the first total synthesis of the cyclic depsipeptides YM-254890 and FR900359, which are the only known specific inhibitors of the Gq subfamily of G proteins; as well as novel analogues1. We also investigated the structure-activity relationships (SAR) that govern Gq selectivity by mutagenesis. These represent unique tools for explorative studies of G protein inhibition, and the SAR brings insight on what may be required to develop selective inhibitors for other G proteins families.

The GPCR database, GPCRdb comprises reference data, online analysis tools and interactive visualisation for receptor structures, crystallisation constructs, sequences, mutants and more2. Recently, a new G protein resource was added to GPCRdb as part of a landmark study on selectivity determinants of GPCR-G protein binding3. This facilitates investigation of GPCR-G protein coupling profiles, interfaces and mutations. Finally, a new project concerning a GPCR biased agonist resource will be presented.

Benefits:
• Which approaches could be explored for structure-based design of G protein inhibitors?
• How can we determine the determinants of GPCR activation states and G protein selectivity?
• How to properly represent biased agonism data to best disseminate and inspire new research?

References:
1. Xiong, X. F.; Zhang, H.; Underwood, C. R.; Harpsoe, K.; Gardella, T. J.; Woldike, M. F.; Mannstadt, M.; Gloriam, D. E.; Brauner-Osborne, H.; Stromgaard, K., Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors. Nature chemistry 2016, 8, 1035-1041.
2. Isberg, V.; Mordalski, S.; Munk, C.; Rataj, K.; Harpsoe, K.; Hauser, A. S.; Vroling, B.; Bojarski, A. J.; Vriend, G.; Gloriam, D. E., GPCRdb: an information system for G protein-coupled receptors. Nucleic Acids Res 2016, 44, D356-64.
3. Flock, T.; Hauser, A. S.; Lund, N.; Gloriam, D. E.; Balaji, S.; Babu, M. M., Selectivity determinants of GPCR-G-protein binding. Nature 2017, 545, 317-322.

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17:30
Investigating Why STK10 is a Common Off-Target of Kinase Inhibitors
 
Jon  Elkins
Jon Elkins
Scientific Director, Structural Genomics Consortium
State University of Campinas
About Speaker: After a PhD in chemistry from the University of Oxford and post-doctoral work in structural biology of proteins involved in the hypoxic response and in antibiotic biosynthesis, Jon now studies proteins involved in cell signalling and disease, especia... Read Full Bio 
 
 
Jon  Elkins
Jon Elkins
Scientific Director, Structural Genomics Consortium
State University of Campinas
 
About Speaker:

After a PhD in chemistry from the University of Oxford and post-doctoral work in structural biology of proteins involved in the hypoxic response and in antibiotic biosynthesis, Jon now studies proteins involved in cell signalling and disease, especially protein kinases. Currently Jon is scientific director of the recently established SGC lab in the State University of Campinas (UNICAMP), Brazil. The focus of SGC-UNICAMP is development of chemical probes for protein kinases, to enable new biological insights and target validation.

 
Abstract: There are now many kinase inhibitors ...Read More 

There are now many kinase inhibitors approved for use as drugs for the treatment of various cancers. A common side-effect of many of these inhibitors, especially those that target the epidermal growth factor receptor (EGFR) for example for non-small-cell lung cancer, is a severe skin rash. This side-effect can be severe enough to necessitate dose-reduction or termination of treatment, and varies significantly in severity between patients. With some EGFR inhibitors such as erlotinib it was observed that presence of the skin rash correlated with a more positive treatment outcome. In several studies a dose-escalation until the onset of severe skin rash yielded superior treatment outcomes. The EGFR inhibition-induced skin rash is characterised by a papulopustular rash involving damaged hair follicles and sebaceous glands and altered keratinocyte differentiation leading to a damaged epidermis. In cases of more severe skin rash there is cytokine release, inflammation, and a large infiltration of leukocytes. It is a reasonable assumption that as dose-escalation yields a more severe skin rash there may be additional kinases inhibited, and one or more of these kinases may be responsible for the unwanted increase in severity of skin disorders and potentially also for the improved treatment outcomes. Previously it was shown that off-target inhibition of STK10 and the related kinase SLK by erlotinib was responsible for the more severe skin disorders observed with erlotinib, as compared to another EGFR inhibitor gefitinib. This fits with the known biology of STK10 and SLK, which are kinases that regulate lymphocyte migration, and are also PLK kinases. We have investigated a set of clinically used kinase inhibitors that bind to STK10. We find that of all the kinases we have tested, STK10 is the most profilic in its ability to bind these inhibitors in vitro. Our aims were to determine how many inhibitors may act via STK10, what are the factors (such as residence) time that might be important, and why STK10 is capable of binding so many different inhibitors.

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17:55
Identification of Potent Inhibitors of the Anti-Infective Target DXS using Ligand-Based Virtual Screening
 
Anna Hirsch
Anna K. H. Hirsch
Professor, Drug Design and Optimization
Helmholtz Institute for Pharmaceutical Research Saarland
About Speaker: Anna Hirsch read Natural Sciences with a focus on Chemistry at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology, doing a research project with Prof. Timothy Jamison on the total synthesis of amphidinol... Read Full Bio 
 
 
Anna Hirsch
Anna K. H. Hirsch
Professor, Drug Design and Optimization
Helmholtz Institute for Pharmaceutical Research Saarland
 
About Speaker:

Anna Hirsch read Natural Sciences with a focus on Chemistry at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology, doing a research project with Prof. Timothy Jamison on the total synthesis of amphidinolide T1.

For her Master’s project, she returned to Cambridge to develop the double conjugate addition of dithiols to propargylic carbonyl systems reaction in the group of Prof. Steven V. Ley.

She received her Ph.D. from the ETH Zurich in 2008. Her research was carried out in the group of Prof. François Diederich and consisted of de novo structure-based design and the synthesis of the first inhibitors for an enzyme as a novel approach to treat malaria.

Subsequently, she joined the group of Prof. Jean-Marie Lehn at the Institut de Science et d’Ingénierie Supramoléculaires (ISIS) in Strasbourg, before taking up a position as assistant professor at the Stratingh Institute for Chemistry at the University of Groningen in 2010. In 2015, she was promoted to associate professor of structure-based drug design. 

In 2017, she moved to the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), where she heads the department for drug design and optimization. Her work focuses on rational approaches to drug design (with a strong focus on anti-infective targets), including structure- and fragment-based drug design in combination with dynamic combinatorial chemistry and kinetic target-guided synthesis. 

Anna Hirsch was awarded the Gratama Science Prize in 2014, the SCT-Servier Prize for Medicinal Chemistry in 2015 and the Innovation Prize for Medicinal Chemistry of the GdCh/DPhG in 2017. 

 
Abstract: The enzymes of the methylerythritol p...Read More 

The enzymes of the methylerythritol phosphate (MEP) pathway are important drug targets given that pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum use this pathway for the biosynthesis of the essential isoprenoid precursors isopentenyl dipohsphate (IPP) and dimethylallyl diphosphate (DMAPP), while humans exclusively utilise an alternative pathway.[1] The thiamine-diphosphate-dependent enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXS) catalyses the first and rate-limiting step of the MEP pathway.

To expand the structural diversity and obtain potent and selective inhibitors of DXS, we performed a ligand-based virtual screening (LBVS) campaign based on shape similarity to screen the ZINC database, starting from previsouly discovered DXS inhibitors as references.[2,3] Biochemical evaluation of the top-scoring compounds against M. tuberculosis DXS and further rounds of LBVS using the best hits as references afforded inhibitors in the single-digit micromolar range. In addition to the promising biochemical activity, the hits are active in cell-based assays against P. falciparum and even drug-resistant strains of M. tuberculosis. Further assays demonstrated their selectivity over mammalian thiamine-diphosphate-dependent enzymes, their lack of cytotoxicity and validated DXS as the intracellular target.[4]

References:
1. Masini T, Hirsch AKH, J. Med. Chem. 2014, 57, 9740–9763.
2. Reymond J-L, Awale M, ACS Chem. Neurosci. 2012, 3, 649–657.
3. Masini T, Pilger J, Kroezen BS, Illarionov B, Lottmann P, Fischer M, Griesinger C, Hirsch AKH, Chem. Sci. 2014, 5, 3543–3551.
4. Hirsch AKH, Reymond J-L, Masini T, Simonin C. EP15160746.2. Manuscript in preparation.

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17:55
Structural Elucidation of Ligand Binding Sites in Class B GPCRs and their Application in Drug Discovery
 
Ali Jazayeri
Ali Jazayeri
CTO
Heptares Therapeutics
About Speaker: Ali joined Heptares in 2007 and as one of the first scientists he was involved in the transfer of the receptor stabilisation (StaR®) technology from MRC Laboratory of Molecular Biology to Heptares. Following successful implementation and industriali... Read Full Bio 
 
 
Ali Jazayeri
Ali Jazayeri
CTO
Heptares Therapeutics
 
About Speaker:

Ali joined Heptares in 2007 and as one of the first scientists he was involved in the transfer of the receptor stabilisation (StaR®) technology from MRC Laboratory of Molecular Biology to Heptares. Following successful implementation and industrialisation of the original technology, he led the development of novel methodologies that significantly increased the efficiency and reach of the StaR® technology. Prior to Heptares, Ali worked as a post-doctoral scientist in Clare Hall Laboratories (a Cancer Research UK institute) and Kudos Pharmaceuticals. In both cases he carried out research on the role of cell cycle checkpoint kinases in DNA damage response pathways. He has a BSc in Genetics from University of Manchester and obtained his PhD in molecular biology with Prof Steve Jackson at the Gurdon Institute from University of Cambridge.

 
Abstract: G protein-coupled receptors (GPCRs) c...Read More 

G protein-coupled receptors (GPCRs) comprise one of the most important families of drug targets owing to the multitude of roles they fulfil across many different physiological processes. Despite the huge amount of investment in GPCR drug discovery there remains significant opportunities for identification of novel or better drugs. One way to achieve this goal is to utilise structure based drug design (SBDD) strategies. However, GPCRs are generally challenging proteins for crystallisation and structure determinations primarily due to their hydrophobic nature, low expression levels and conformational flexibility. To facilitate application of SBDD approaches to GPCRs Heptares uses its proprietary StaR technology to thermostabilise GPCRs in a single conformational state. The purified StaRs can then be used for crystallisation to yield X-ray structures with multiple ligands as well as used in biophysical screening techniques. Using the StaR approach, we have solved structures of multiple Class B GPCRs in both agonist and antagonist conformations. This has led to the elucidation of the orthosteric and allosteric binding sites. The structural insight into multiple ligand binding sites has significantly increased our ability to design novel drugs to modulate the activities of these receptors.

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17:55
Broad-Spectrum Kinase Profiling of Kinetic and Thermodynamic Selectivity in Live Cells
 
Matthew Robers
Matthew Robers
Senior Research Scientist and Group Leader
Promega
About Speaker: Matthew Robers is a Senior Research Scientist and Group Leader at Promega Corporation. Matthew received his B.S. Degree in the Dept. of Genetics and his M.S. Degree in the Department of Bacteriology at the University of Wisconsin - Madison. Matthew h... Read Full Bio 
 
 
Matthew Robers
Matthew Robers
Senior Research Scientist and Group Leader
Promega
 
About Speaker:

Matthew Robers is a Senior Research Scientist and Group Leader at Promega Corporation. Matthew received his B.S. Degree in the Dept. of Genetics and his M.S. Degree in the Department of Bacteriology at the University of Wisconsin - Madison. Matthew has authored over 20 peer-reviewed publications and published patents on the application of novel assay chemistries to measure intracellular protein dynamics. Matthew's team currently focuses on the development of new technologies to assess target engagement, and has developed a biophysical technique for quantifying compound affinity and residence time at selected targets within intact cells.

 
Abstract: Intracellular target selectivity is f...Read More 

Intracellular target selectivity is fundamental to pharmacological mechanism. Although a number of acellular techniques have been developed to quantitatively measure kinase binding or enzymatic inhibition, currently no biophysical approaches exist that offer quantitative analysis of target affinity or residence time across the human kinome in live cells. Here we report the application of an energy transfer technique (NanoBRET) that enabled the first quantitative approach to broadly profile kinase occupancy under equilibrium and non-equilibrium conditions. This approach enabled a mechanistic interrogation of the potency offsets observed between cellular and acellular analysis of kinase engagement. Compared to published biochemical profiling results, an improved intracellular selectivity profile was observed for certain promiscuous kinase inhibitors, and a number of putative drug targets are unexpectedly disengaged in live cells at a clinically-relevant drug dose. The energy transfer technique can also be performed in real time, enabling broad-spectrum assessments of compound residence time. Profiling of kinase occupancy under equilibrium and non-equilibrium conditions reveals surprising kinetic selectivity mechanisms for certain multi-kinase inhibitors.

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18:20
Networking Reception & Poster Session
ssclaas=mixsessionprlval=1Array ( [3173] => 1 )
Day - 2 Friday, November 17th, 2017
 
8:00
Breakfast at Restaurant (included for those staying at the Radisson Blu)
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Drug Design & Medicinal Chemistry
Epigenetic Based Inhibitors
Moderator: Sharad Verma, Johns Hopkins University School of Medicine
9:00
The Design and Optimization of Orally Bioavailable EZH2 Inhibitors
 
Steven  Knight
Steven Knight
Scientific Leader, Cancer Epigenetics Discovery Performance Unit
GSK
About Speaker: Dr. Steven Knight is a Scientific Leader at GlaxoSmithKline. His career has spanned over 21 years at GSK, where he has led multiple program teams to deliver clinical candidates, including inhibitors of the PI3K pathway and mitotic kinesins. Dr. Knigh... Read Full Bio 
 
 
Steven  Knight
Steven Knight
Scientific Leader, Cancer Epigenetics Discovery Performance Unit
GSK
 
About Speaker:

Dr. Steven Knight is a Scientific Leader at GlaxoSmithKline. His career has spanned over 21 years at GSK, where he has led multiple program teams to deliver clinical candidates, including inhibitors of the PI3K pathway and mitotic kinesins. Dr. Knight received a B.S. in chemistry from the University of California, Berkeley, a Ph.D. from the University of California, Irvine, and did postdoctoral studies as a NIH fellow at the University of Pennsylvania.

 
Abstract: The Design and Optimization of Orally...Read More 

The Design and Optimization of Orally Bioavailable EZH2 inhibitors The EZH2 histone methyltransferase is frequently mutated in diffuse large B-cell lymphoma leading to increased trimethylation of histone H3 lysine 27 (H3K27me3). Drug discovery efforts have previously identified GSK126, a potent and selective inhibitor of EZH2 catalytic activity. GSK126 is currently being evaluated as a clinical oncology agent, however, it requires administration through a central IV port. Through medicinal chemistry optimization, we have developed second generation EZH2 inhibitors with significantly improved potency and physicochemical properties. More importantly, these compounds exhibit excellent in vivo activity following oral administration in mouse xenograft models. Benefits: • Design of compounds with improved developability properties (solubility, etc.) • Using predictive assays to introduce and maximize oral bioavailability • Overcoming selectivity issues • Lead optimization strategy in a fiercely competitive environment

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GPCR Targeted Screening
GPCR Structure-Based Drug Discovery
Moderator: Philippe Marin, CNRS
9:00
Navigating Chemical Space in Search for Selective GPCR Ligands
 
Peter  Kolb
Peter Kolb
Professor
University of Marburg
About Speaker: Peter Kolb is a Heisenberg Professor of Pharmaceutical Chemistry at Philipps-University Marburg. He has joind UMR as an Emmy Noether junior group leader in 2011. His research centers on computer-aided ligand discovery. The current focus is on G prote... Read Full Bio 
 
 
Peter  Kolb
Peter Kolb
Professor
University of Marburg
 
About Speaker:

Peter Kolb is a Heisenberg Professor of Pharmaceutical Chemistry at Philipps-University Marburg. He has joind UMR as an Emmy Noether junior group leader in 2011. His research centers on computer-aided ligand discovery. The current focus is on G protein-coupled receptors and method development for fragment-based drug discovery. Prior to his appointment at UMR, he was a postdoctoral fellow at the University of California, San Francisco. Peter holds a Ph.D. in Computational Biochemistry from the University of Zurich and an M.Sc. in Chemistry from the University of Vienna. From 2013-2017, he was chair of COST Action CM1207 "GLISTEN", which united more than 200 GPCR researchers from 31 different countries.

 
Abstract: I will highlight key lessons learned ...Read More 

I will highlight key lessons learned from docking multi-million compound libraries to different GPCRs. The most prominent example is the first unbiased screen we did with the β2-adrenergic receptor, which produced six novel binders – some of them with chemotypes previously undescribed for this target – and a most potent compound with an affinity of 9 nM.

I will also show how we identified derivatives of these compounds, further elaborating on the unprecedented chemotypes. Further examples include the chemokine receptors CXCR3 and CXCR4, where we identified potent ligands with tailored selectivity profiles with hit rates exceeding 50 %. I will also present a database of virtual compounds optimized towards high likelhood of synthetic tractability, called SCUBIDOO. It currently holds 21 M compounds, based on approx. 8000 building blocks, thus opening up large areas of chemical space. Twohundred compounds have already been synthesized and tested in biochemical assays, demonstrating the validity and potential of the approach. I will show compounds that have been designed for the β2-adrenergic receptor.

Benefits:
– learn about screening with selectivity questions in mind
– find out about strategies to make chemical space accessible
– appreciate the potential of structure-based ligand design methods

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Kinase Inhibitors in Drug Discovery
Overcoming Therapeutic Resistance
Moderator: Pedro Cutillas, Queen Mary University of London
9:00
The Oncogenic Effects of PI3K Activation: Therapeutic Implications of Unexpected Functions
 
Igor Vivanco
Igor Vivanco
Team Leader
Institute of Cancer Research
About Speaker: A native of Peru, Dr Vivanco received his BA in Molecular and Cellular Biology from the University of California at Berkeley, and his PhD in Molecular Biology from the University of California at Los Angeles under Dr. Charles Sawyers. Dr Vivanco comp... Read Full Bio 
 
 
Igor Vivanco
Igor Vivanco
Team Leader
Institute of Cancer Research
 
About Speaker:

A native of Peru, Dr Vivanco received his BA in Molecular and Cellular Biology from the University of California at Berkeley, and his PhD in Molecular Biology from the University of California at Los Angeles under Dr. Charles Sawyers. Dr Vivanco completed postdoctoral training in the laboratory of Dr Ingo Mellinghoff at Memorial Sloan Kettering Cancer Center, where he focused on the study of oncogenic EGFR and PI3K signalling. In 2014, he moved to the Institute of Cancer Research in London, where he leads Molecular Addictions team in the Division of Cancer Therapeutics. His laboratory studies the molecular basis of PI3K addiction in a variety of tumours with a particular focus on understanding the contribution of non-catalytic functions of AKT and other AGC kinases to PI3K-dependent cell survival.

 
Abstract: Aberrant activation of the PI3K pathw...Read More 

Aberrant activation of the PI3K pathway is one the most common oncogenic events in human tumours. The clinical success and regulatory approval of idelalisib, a PI3Kδ inhibitor, for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin’s lymphoma, validate the importance of the pathway in human malignancies. However, compared to the high frequency of PI3K activation in human cancer, response rates to other PI3K-targeted therapies remain low, highlighting the need for a better understanding of how PI3K-dependent signals regulate cell survival in specific genetic contexts. Whether PI3K itself is an oncogenic driver in human tumours, or whether it acts as an “active passenger” (i.e. one that influences the functional output of the driver), will determine its potential as a therapeutic target.

The serine/threonine kinase Akt is a critical PI3K effector that promotes a number of cancer-associated phenotypes, including cell survival. Consequently, a number of pharmacological agents directly targeting Akt have been developed and are currently undergoing clinical evaluation. However, the clinical experience so far has been disappointing, suggesting that either AKT is not the only (or the primary) PI3K-dependent effector responsible for cell survival in PI3K-active tumours, or that pharmacological approaches have been inadequate. Our work has focused on understanding the contribution of PI3K to cancer cell survival in a variety of cell-type- and genetic-specific contexts. We have also been interested in using comparative pharmacology to probe different aspects of PI3K and AKT function to understand how these signals are transduced into cell survival effects. I will discuss our efforts to better understand PI3K/AKT-dependent regulation of cancer cell survival.

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9:25
Histone Methyltransferases as Therapeutic Targets in Neuroblastoma
 
Karim Malik
Karim Malik
Reader & Associate Professor, Epigenetics, School of Cellular & Molecular Medicine
University of Bristol
About Speaker: Currently, I am a Reader/Associate Professor in Epigenetics, School of Cellular & Molecular Medicine, University of Bristol. My main area of research is paediatric solid tumours, especially neuroblastoma and Wilms’ tumour. My interests include ... Read Full Bio 
 
 
Karim Malik
Karim Malik
Reader & Associate Professor, Epigenetics, School of Cellular & Molecular Medicine
University of Bristol
 
About Speaker:

Currently, I am a Reader/Associate Professor in Epigenetics, School of Cellular & Molecular Medicine, University of Bristol. My main area of research is paediatric solid tumours, especially neuroblastoma and Wilms’ tumour. My interests include is histone methyltransferases as potential drug targets and signaling pathways in neuroblastoma. Our work is currently funded by Cancer Research UK, Neuroblastoma UK – Smile with Siddy, the Childrens Cancer and Leukaemia Group and the Biotechnology and Biological Sciences Research Council (BBSRC).

 
Abstract: Neuroblastoma is a very heterogeneous...Read More 

Neuroblastoma is a very heterogeneous childhood cancer that includes a poor prognosis subset for which new therapeutic agents are urgently required. This subset is defined by amplification of the MYCN oncogene. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. However, these mutations occur at low levels and there remains a paucity of druggable oncogenic targets. We therefore investigated the possibility that epigenetic modulators might be key drivers of tumorigenesis in this cancer. Here we report our analysis of these targets, including G9a and PRMT5, as potential druggable entities for novel neuroblastoma therapeutics. We show that, as well as exerting epigenetic effects, histone methyltransferases may have profound influences on neuroblastoma biology via post-translational modification of non-histone proteins, including MYCN. Thus small molecule inhibitors of HMTs may represent promising agents for treatment of high risk neuroblastoma.

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9:25
DNA-Encoded Library Screening on a GPCR: Identification of Agonists and Antagonist to PAR2 with Novel and Diverse Mechanisms of Action
 
Niek  Dekker
Niek Dekker
Principal Scientist, Discovery Biology
AstraZeneca
About Speaker: Professional career 2012-present Principal scientist in Reagents & Assay Development, Discovery Sciences 2008-2012 Delivery Leader to central nervous system and pain (CNS&P) iMed, Cell, Protein & Structural Sciences, Discovery Enabling Ca... Read Full Bio 
 
 
Niek  Dekker
Niek Dekker
Principal Scientist, Discovery Biology
AstraZeneca
 
About Speaker:

Professional career 2012-present Principal scientist in Reagents & Assay Development, Discovery Sciences 2008-2012 Delivery Leader to central nervous system and pain (CNS&P) iMed, Cell, Protein & Structural Sciences, Discovery Enabling Capabilities and Sciences, Mölndal, AstraZeneca-R&D, Sweden 2004-2008 Associate Director Protein Engineering Section, Structural Chemistry Laboratories, Mölndal, AstraZeneca-R&D, Sweden 2000-2004 Team Leader Protein Engineering, Structural Chemistry Laboratories-Mölndal, AstraZeneca-R&D, Sweden. 1994-2000 Assistant Professor Utrecht University, the Netherlands. Education 1993 EMBL-funded postdoctoral fellow molecular biology (ETH-Zurich, Switzerland) 1992 postdoctoral fellow NMR spectroscopy (Utrecht University, the Netherlands) 1987-1991 PhD Enzymology (Chemistry faculty, Utrecht University, the Netherlands) 1981-1986 Chemistry Master studies

 
Abstract: Protease-activated receptor-2 (PAR2) ...Read More 

Protease-activated receptor-2 (PAR2) is irreversibly activated by proteolytic cleavage of the N-terminus which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain eliciting a cellular cascade in response to inflammatory signals and other stimuli. PAR2 is implicated in a wide range of inflammatory and other diseases including cancer. Activation of PAR2 on sensory neurons leads to hyperphophorylation of TRP channels resulting in pain and hyperalgesia. The discovery of small molecule antagonists to PAR2 has proven challenging. DNA-encoded library (DEL) screening on purified PAR2 delivered both antagonists and agonists, exemplified by AZ3451 (SLIGRL PAR2 IP-one IC50 = 23 nM) and AZ8838 (SLIGRL PAR2 IP-one IC50 = 1500 nM), and agonist AZ2429 (EC50 of 53 nM in IP-one). Crystal structures of antagonist bound to the GPCR revealed that AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. AZ3451 and AZ8838 were tested in a rat model of PAR2-induced oedema using 2fLIGRL-NH2 (350 µg/paw in 100 µL and trypsin (20 µg/ paw in 100 µL). At a 10 mg/kg dose, both compounds exhibited reduction of paw swelling in both in vivo models. These results confirm that at least two allosteric sites exist on the PAR2 receptor and can be blocked resulting in reversal of in vitro and in vivo PAR2 mediated signaling. DEL screening on purified PAR2 combined with crystallography provided a basis for the development of selective PAR2 antagonists for a range of therapeutic indications. Benefits: Learning about an integrated approach to GPCR drug discovery using purified GPCR and various hit finding approaches (FBLG, DEL)

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9:25
Discovery of an Efficacious and Selective MEK Inhibitor with ATP-Competitive Mode of Action
 
Henrik  Moebitz
Henrik Moebitz
Senior Investigator, Global Discovery Chemistry
Novartis
About Speaker: Henrik Möbitz is currently group leader and Senior Research Investigator, Global Discovery Chemistry at Novartis. In this role, he has lead medicinal chemistry projects and external collaborations. Prior to this, he studied enzyme mechanisms by use ... Read Full Bio 
 
 
Henrik  Moebitz
Henrik Moebitz
Senior Investigator, Global Discovery Chemistry
Novartis
 
About Speaker:

Henrik Möbitz is currently group leader and Senior Research Investigator, Global Discovery Chemistry at Novartis. In this role, he has lead medicinal chemistry projects and external collaborations. Prior to this, he studied enzyme mechanisms by use of biochemistry (PhD at Albert-Ludwigs-Universität Freiburg in 2003) and simulation (Postdoctoral Fellow at UC Santa Barbara). Recent research projects target epigenetic methyl transferases, helicases, kinases and the MAPK pathway in particular, with a focus on integrating structure based design and data analysis.

 
Abstract: Mutations in MEK1/2 have been describ...Read More 

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK inhibitor with efficacy in WT and mutant MEK models. Starting from an HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK and a panel of MEK mutant cell lines. Using a structure based approach, the optimisation addressed the liabilities of the series (poor physicochemical properties, Cyp3A4 inhibition and a species disconnect in clearance) by systematic analysis of matched pairs and the impact of ligand conformation. With the addition of only 3 heavy atoms, we were able to remove liabilities and increase cellular potency 100-fold, while reducing logP by 5 units.

Profiling of compound 30 in PK-PD and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK inhibitors. Compound 30 is a novel highly potent and selective MEK1 kinase inhibitor with equipotent inhibition of WT and mutant MEK whose drug like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.

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9:50
Selective BET Bromodomain Inhibition as a Potential Antifungal Therapeutic Strategy
 
Jérôme Govin
Jérôme Govin
Independent Team Leader, Biosciences and Biotechnology Institute of Grenoble
University Grenoble Alpes
About Speaker: Dr Govin has been deciphering chromatin signaling pathways in various physiological and pathological contexts. Using model organisms, his work has been revealing molecular mechanisms and inspiring new translational approaches in biomedical research.... Read Full Bio 
 
 
Jérôme Govin
Jérôme Govin
Independent Team Leader, Biosciences and Biotechnology Institute of Grenoble
University Grenoble Alpes
 
About Speaker:

Dr Govin has been deciphering chromatin signaling pathways in various physiological and pathological contexts. Using model organisms, his work has been revealing molecular mechanisms and inspiring new translational approaches in biomedical research.

 
Abstract: Invasive fungal infections cause sign...Read More 

Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. We investigated a chromatin-interacting module, the bromodomain from the BET family of proteins, as a potential antifungal target in pathogenic yeasts. We show that the BET protein Bdf1 is essential in Candida albicans and that mutations inactivating its two bromodomains result in a loss of viability in vitro and decreased virulence in mice. Using high- throughput chemical screening, we identified compounds that inhibit C. albicans Bdf1 in vitro with high selectivity over human bromodomains. Crystal structures of the Bdf1 bromodomains reveal binding modes for these inhibitors that are sterically incompatible with the human BET binding pockets. Furthermore, we identified a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 bromodomain-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

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9:50
GPCR - G Protein Selectivity Determined by Interaction Kinetics
 
Moritz  Bünemann
Moritz Bünemann
Professor, Pharmacology and Clinical Pharmacy
University of Marburg
About Speaker: Moritz Bünemann studied biology at the University of Bochum, where he also received his Dr. rer. nat in Cellular Physiology (1996) working on GPCR desensitization and sphingolipid receptor identification and its role in signaling. He completed a pos... Read Full Bio 
 
 
Moritz  Bünemann
Moritz Bünemann
Professor, Pharmacology and Clinical Pharmacy
University of Marburg
 
About Speaker:

Moritz Bünemann studied biology at the University of Bochum, where he also received his Dr. rer. nat in Cellular Physiology (1996) working on GPCR desensitization and sphingolipid receptor identification and its role in signaling. He completed a postdoctoral fellowship with Marlene Hosey, Northwestern University Medical School, Chicago, USA, working on GPCR Pharmacology and Calcium channel regulation (1996-2000), He went back to start as an advanced postdoc with Martin Lohse at the University of Wuerzburg where he worked on the development of FRET-based real time assays to study GPCR function and signaling. He was promoted to a group leader and later Associate Professor for Molecular Pharmacology at University of Wuerzburg (2008-2009), In 2009 he was appointed as Professor and Chair of the Department of Pharmacology and Clinical Pharmacy, University of Marburg. Since then he worked on topics such as voltage sensitivity of GPCRs, GPCR dimerization, GPCR desensitization, GRK-Receptor interactions, GPCR-G protein recognition as well as G protein signaling in real time of various pathways.

 
Abstract: G protein coupled receptors regulate ...Read More 

G protein coupled receptors regulate many physiological processes by coupling to 4 classes of heterotrimeric G proteins. The total pool of 16 Galpha subunits can be divided into these classes based on their degree of homology and downstream coupling. Whereas some GPCRs almost exclusively couple to preferred subtypes of only one class of G proteins, many GPCRs can activate G proteins of more then one class. Due to the lack of suitable assays to quantify GPCR coupling selectivity and GPCR – G protein interactions in biological membranes determinants of the G protein selectivity on the level of GPCRs are missing. In accordance with ternary complex model we hypothesized that the affinity of the G protein to the receptor in the nucleotide-free state determines the selectivity of GPCR-G protein coupling. We therefore attempted to measure receptor-G protein complex formation in single permeabilized cells under conditions of GTP-depletion by means of FRET. In order to get more insight into the relative binding affinities we compared binding of G proteins to GPCRs dependent on the different Ga subunits expressed. As a model system we used M3 muscarinic receptors for which we observed coupling to both Gi/o and Gq proteins but not to Gs and G12/13. Our results show that the affinity of M3 receptors to Gq was about 15 fold higher than to Gi/o protein. This difference was almost exclusively attributable to differences in the dissociation kinetics of the complex, whereas the on rate was very similar. Importantly, we measured also the coupling efficiency of these receptors to Gq and Go proteins in intact cells at the level of G proteins and found that the difference in G protein binding affinity correlated directly with the coupling efficiency. Conclusion and Benefits: 1. we developed an broadly applicable assay to quantify GPCR – G protein interactions in a native membrane environment. 2. Binding kinetics of the GPCR – G protein complex can be resolved in a receptor and G protein specific manner in membranes of single cells. 3. Dissociation kinetics of the ternary complex determine the affinity. 4. The steady state affinity of the GPCR – G protein complex but not the association kinetics quantitatively correlate with the G protein subtype specific coupling efficiency

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9:50
Overcoming Drug-Resistant EGFR Mutants with Allosteric Inhibitors
 
Michael  Eck
Michael Eck
Professor, Biological Chemistry & Molecular Pharmacology
Harvard Medical School
About Speaker: Dr. Eck received his M.D. and Ph.D. from the University of Texas Southwestern Medical School and trained as a postdoctoral fellow with Dr. Stephen Harrison at Children’s Hospital and Harvard Medical School before joining the DFCI in 1996. His resea... Read Full Bio 
 
 
Michael  Eck
Michael Eck
Professor, Biological Chemistry & Molecular Pharmacology
Harvard Medical School
 
About Speaker:

Dr. Eck received his M.D. and Ph.D. from the University of Texas Southwestern Medical School and trained as a postdoctoral fellow with Dr. Stephen Harrison at Children’s Hospital and Harvard Medical School before joining the DFCI in 1996. His research focuses on the structure and regulation of tyrosine kinases in cancer and on structure-based approaches to discovery of novel inhibitors.

 
Abstract: Mutations in the kinase domain of the...Read More 

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a major cause of lung adenocarcinoma, and tyrosine kinase inhibitors (TKIs) targeting the receptor are effective treatments for tumors driven by these mutations. The long-term efficacy of current EGFR inhibitors is compromised by secondary resistance mutations, in particular the T790M “gatekeeper” mutation that confers resistance to first and second generation EGFR inhibitors. Resistance due to T790M can be overcome with the third generation inhibitor osimertinib, which is a mutant-selective inhibitor that binds irreversibly via formation of a covalent bond with C797 at the edge of the ATP-site. Unfortunately, clinical resistance to osimertinib has already been observed due to mutation of this cysteine residue (C797S).

All current EGFR TKIs bind the ATP-site of the kinase, highlighting a need for discovery of inhibitor classes with alternate mechanisms of action and binding sites. We are using structural and mechanistic insights to develop mutant-selective allosteric inhibitors of mutant EGFR. We previously described EAI045, a ~3 nM inhibitor of L858R/T790M mutant EGFR in biochemical assays with ~1000-fold selectivity versus the wild type receptor. The compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. While this compound alone is not effective in blocking EGFR-driven proliferation (due to differing potency on the two subunits of the EGFR asymmetric dimer), it exhibits dramatic synergy in combination with cetuximab, an anti-EGFR antibody that blocks receptor dimerization and thus renders the kinase uniformly susceptible to the allosteric inhibitor. We have now developed a more potent allosteric inhibitor that is active as a single agent in a genetically engineered mouse model of L858R/T790M/C797S EGFR lung adenocarcinoma, a genotype that is resistant to all other EGFR-targeted therapies.

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10:15
Lead Finding for Lysine Methyltransferases – SMYD2 and Beyond
 
Ingo  Hartung
Ingo Hartung
Director, Drug Discovery, Medicinal Chemistry Berlin
Bayer AG
About Speaker: Dr. Ingo Hartung is director for medicinal chemistry at Bayer AG in Berlin and in this role responsible for Bayer’s early research portfolio in the field of immunooncology. Prior to this he lead Bayer’s activities in developing epigenetic probes ... Read Full Bio 
 
 
Ingo  Hartung
Ingo Hartung
Director, Drug Discovery, Medicinal Chemistry Berlin
Bayer AG
 
About Speaker:

Dr. Ingo Hartung is director for medicinal chemistry at Bayer AG in Berlin and in this role responsible for Bayer’s early research portfolio in the field of immunooncology. Prior to this he lead Bayer’s activities in developing epigenetic probes in collaboration with the Structural Genomics Consortium. Dr. Hartung joined Bayer (via Schering AG) in 2004 and led optimization projects both in oncology as well as in cardiology. From 2011 to 2015 Dr. Hartung was head of microbiological chemistry at Bayer Healthcare AG. His research interests cover the field of oncology drug discovery, innovation in medicinal chemistry and the use of biocatalysis in life sciences. Dr. Hartung studied chemistry at University of Hannover/Germany and Stanford University/USA and was a postdoctoral fellow in biochemistry at Stanford University. He is a lecturer for medicinal chemistry at the Technical University Berlin/Germany and member of the American Association for Cancer Research (AACR) and the Gesellschaft Deutscher Chemiker (GDCh).

 
Abstract: One in two men and one in three women...Read More 

One in two men and one in three women in the industrialized western world will be diagnosed with cancer in their lifetime. Despite significant advances in the understanding of tumor biology curative treatments or life-extending therapies are urgently needed for the deadliest forms of cancer. Limited reproducibility of published target validation studies has been recognized as one road block for de novo cancer target discovery. The use of unspecific low-quality tool inhibitors for cellular target validation purposes is contributing to this situation. The Structural Genomics Consortium (SGC), a public-private partnership that supports the discovery of new medicines through open access research, addresses this issue by developing high quality small molecular probes for novel targets of interest. Here, I will outline probe discovery challenges and key success factors based on two case studies out of the field of cancer epigenetics.

SMYD2 is a protein methyltransferase which has been described as a regulator of the tumor suppressor p53 and is overexpressed is various solid tumor types. High-throughput screening of three million compounds followed by state-of-the-art hit-to-lead and lead optimization efforts led to the discovery of BAY-598. BAY-598 is a highly selective, cellularly active and orally bioavailable inhibitor of SMYD2. The related lysine methyltransferase SMYD3 was postulated to play a role in MAPK signaling in Ras-mutated tumor cells. Building on key learnings from our SMYD2 inhibitor program, we were able to identify an unprecedented series of SMYD3 inhibitors which was optimized to the potent and selective SMYD3 probe BAY-6035.

I will discuss key success factors and lessons learned from these two projects which have high relevance for lead finding activities within the family of methyltransferases and beyond.

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10:15
Directed Evolution of G Protein-Coupled Receptors for Improved Expression and Stability
 
Christoph  Klenk
Christoph Klenk
Postdoctoral Fellow, Biochemistry
University of Zurich
About Speaker: Christoph Klenk, M.D. Ph.D., is a postdoctoral research fellow at the Department of Biochemistry, University of Zurich. He received a M.D. degree and a Ph.D. degree in molecular pharmacology from University of Würzburg, Germany. Dr. Klenk intensivel... Read Full Bio 
 
 
Christoph  Klenk
Christoph Klenk
Postdoctoral Fellow, Biochemistry
University of Zurich
 
About Speaker:

Christoph Klenk, M.D. Ph.D., is a postdoctoral research fellow at the Department of Biochemistry, University of Zurich. He received a M.D. degree and a Ph.D. degree in molecular pharmacology from University of Würzburg, Germany. Dr. Klenk intensively studied the function of G protein-coupled receptors with a focus on activation and signaling mechanisms of the parathyroid hormone receptor, one of the key targets for osteoporosis therapy. Recently, he joined the lab of Prof. Andreas Plückthun at University of Zurich to investigate the structure-function relationship of G protein-coupled receptor signaling.

 
Abstract: Despite their tremendous pharmacologi...Read More 

Despite their tremendous pharmacological relevance and potential for the development of new drugs, our understanding of G protein-coupled receptor (GPCR) architecture and signaling mechanisms are still limited. Major reasons for this are the low abundance and poor biophysical properties of GPCRs, which makes them one of the most challenging class of proteins for structural and biophysical studies. To overcome these limitations, we have developed several methods for improving functional expression and simultaneous thermo-stabilization of GPCRs by directed evolution. By this strategy, key residues within a receptor sequence can be rapidly identified that are responsible for improved biophysical properties. Here I will present the key concepts how GPCRs can be stabilized with directed evolution. Moreover, I will present our recent efforts to thermo-stabilize the human parathyroid hormone 1 receptor (PTH1R), which is the major regulator of calcium homeostasis and bone metabolism in the human body and a primary target for the treatment of osteoporosis.

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10:15
EGFR Triple Mutant: Recent Set-Backs and New Hopes in Fighting Mutant Non-Small Cell Lung Cancer
 
Stefan  Laufer
Stefan Laufer
Chairman Pharm. & Medicinal Chemistry, Department Pharmacy & Biochemistry
University of Tübingen
About Speaker: Chemistry Stefan Laufer, is Professor for Pharmaceutical/Medicinal Chemistry at Tuebingen University. He received his degrees from Regensburg University. After 10 years in Pharmaceutical Industry (Head Drug Research, R&D Director Merckle GmbH) he... Read Full Bio 
 
 
Stefan  Laufer
Stefan Laufer
Chairman Pharm. & Medicinal Chemistry, Department Pharmacy & Biochemistry
University of Tübingen
 
About Speaker:

Chemistry Stefan Laufer, is Professor for Pharmaceutical/Medicinal Chemistry at Tuebingen University. He received his degrees from Regensburg University. After 10 years in Pharmaceutical Industry (Head Drug Research, R&D Director Merckle GmbH) he joined in 1999 Tuebingen University as Chairman Pharm./Med. Chemistry. His research interests are anti-inflammatory and cancer drug discovery with various eicosanoid (COX-1,2,3, LOXs, mPGES1, cPLA2) and protein kinase targets (p38, JAKs, JNKs, CK1d, mtEGRFs) . Three compounds from his lab entered clinical development phases. Dr. Laufer chairs the ICEPHA (Interfaculty Center for Pharmacogenomics and Drug Research) and TüCADD, Tuebingen Center for Academic Drug Discovery. As part of this work, a proprietary kinase inhibitor collections is established (TüKIC, 7000 cpds). He authored more than 380 publications, 15 books/bookchapters and is inventor in 42 patent families.

 
Abstract: The discovery of EGFR L858R and del19...Read More 

The discovery of EGFR L858R and del19 activating mutations in non-small cell lung cancer patients intensified the change of thinking towards personalized tumor therapy. “Oncogene addiction” to the EGFR signalling pathway paved the way for the development of the small molecules erlotinib and gefitinib as mutant selective, first generation tyrosine kinase inhibitors. Initial good results were overshadowed by imminent resistance development mainly via the gatekeeper point mutation T790M. Rational efforts in drug design finally led to irreversible third generation, mutant selective EGFR inhibitors with promising results in patient with acquired T790M mutations that became resistant to first generation TKIs. Recently, a third point mutation C797S was discovered in the cancer tissue of patients. This particular mutation renders irreversible bond formation with the cysteine impossible. Thus this acquired mutation leads to resistance to the actual gold standard osimertinib (FDA-approved 2015). Beside the development of potent allosteric inhibitors, a target hopping approach from yridinylimidazole-based p38 MAPK inhibitors to EGFR inhibitors led to trisubstituted imidazoles as structural novel class of EGFR-inhibitors. The approach yielded very potent reversible and irreversible inhibitors of the EGFR L858R, L858R/T790M and L858R/T790M/C797S mutants with submicromolar IC50s. These compounds show apart from a covalent binding mode to the double mutant additional noncovalent binding properties at the triple mutant. Furthermore, high cellular as well as wild type sparing activity (comparable to osimertinib) in L858R/T790M mutant cancer cell lines, good kinome selectivity profile and metabolic stability could be achieved. Example compound shows IC50 (EGFR-L858R/T790M) = < 0.5 nM and EGFRL858R/T790M/C797S down to 6 nM. Cellular EC50 value reaches down to 6 nM in a double mutant L858R/T790M cell line. In sum, this new class of EGFR inhibitors together with this rational approach to inhibit EGFR L858R/T790M/C797S may stimulate the development of either improved trisubstituted imidazoles as candidates or probes.In addition the design approach might be transfered to other structural classes of EGFR inhibitors.

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10:40
Morning Networking Break
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Round Table Discussions
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11:10
Round Table Topics
 

1 | Fit for the Future? Current Challenges and Bottlenecks in the Drug Discovery Process | Chair: Frank Boeckler, Eberhard Karls Universität Tübingen 

 

2 | Machine Learning: Promise or Hype? | Chair: Matthias Rarey, Universität Hamburg

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11:10
Round Table Topics
 

1 | The GPCR Structural Revolution: What Lies Ahead? | Chair: Niek Dekker, AstraZeneca

 

2 | Signaling Bias in Drug Discovery | Chair: Ann de Blieck, Confo Therapeutics

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11:10
Round Table Topics
 

1 | Allosteric Inhibitors, Pros & Cons, and Strategies to Obtain them | Chair: Daniel Lietha, Spanish National Cancer Research Centre (CNIO)

 

2 | Optimization of Binding Kinetics: Facts or Fantasy? | Chair: Stefan Laufer, University of Tübingen

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12:30
Lunch Provided by GTCbio
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14:35
Summit Concludes