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Enzymes in Drug Discovery Summit

2018-02-182018-01-092017-10-27
Register 3 for the price of 2 with the coupon code rcdvb!


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Day 1 - Thursday, February 22, 2018
7:30
Continental Breakfast and Registration
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8:15
Welcome & Opening Remarks
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10:00
Morning Networking Break
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Protein Kinases in Drug Discovery
Novel Approaches, Tools and Technologies in Kinase Drug Discovery
Moderator: Alexandra Newton, UC San Diego
10:45
Multiscale Network Modeling and Systems Biology Analysis of Protein Kinase Regulation by the Hsp90-Cdc37 Chaperone: Towards Rational Allosteric Targeting of Protein Kinases by Chaperone Inhibitors
 
Gennady Verkhivker
Gennady Verkhivker
Professor, Computational Biosciences & Translational Medicine
Schmid College of Science & Technology, Chapman University
About Speaker: Dr. Verkhivker is currently Professor of Computational Biosciences and Translational Medicine at Chapman University and Adjunct Professor of Pharmacology at the Department of Pharmacology, UC San Diego. He received his PhD in Physical Chemistry from ... Read Full Bio 
 
 
Gennady Verkhivker
Gennady Verkhivker
Professor, Computational Biosciences & Translational Medicine
Schmid College of Science & Technology, Chapman University
 
About Speaker:

Dr. Verkhivker is currently Professor of Computational Biosciences and Translational Medicine at Chapman University and Adjunct Professor of Pharmacology at the Department of Pharmacology, UC San Diego. He received his PhD in Physical Chemistry from Moscow University and completed a postdoctoral fellowship in computational biophysics from University of Illinois at Chicago in 1992. Dr. Verkhivker was one of the founding scientists at Agouron Pharmaceuticals Inc, in early 1990s and played a leading role in establishing computer-aided structure-based design technology. In 1993-2006, Dr. Verkhivker has held various research and management positions at Agouron Pharmaceuticals, Warner- Lambert, Pfizer Global Research and Development, La Jolla Laboratories. Since 2002, he has been Adjunct Professor of Pharmacology at the Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego. In 2006, he joined School of Pharmacy and Center for Bioinformatics, The University of Kansas as a Full Professor of Pharmaceutical Chemistry and Bioinformatics. In 2011 Dr. Verkhivker assumed position of Full Professor of Computational Biosciences & Translational Medicine at Schmid College of Science & Technology and Professor at the Department of Biomedical and Pharmaceutical Sciences at Chapman University School of Pharmacy. Dr. Verkhivker authored more than 150 peer reviewed publications and is recognized for his research contributions in the fields of translational bioinformatics, computational biophysics and structure-based drug discovery of molecularly targeted and personalized anti-cancer agents. His most recent research activities are in the areas of computational systems biology, translational bioinformatics and systems pharmacology with the focus on integration of computational and experimental systems biology approaches in translational research.

 
Abstract: The synergistic roles of the Hsp90-Cd...Read More 

The synergistic roles of the Hsp90-Cdc37 chaperone machinery and protein kinases in biology and disease have stimulated   extensive structural and functional studies of   regulatory mechanisms underlying the Hsp90-kinase interactions. Allosteric   interactions of the Hsp90 with cochaperones and protein kinase clients can determine   regulatory mechanisms and cellular functions of many signaling proteins and cascades.  We report the results of an integrative biology study that examined these mechanisms at the molecular level by combining    multiscale modeling of conformational landscapes for the protein kinases clients with systems biology analysis and biophysical characterization of the chaperone-kinase interactions. Our study provides evidence that the Hsp90-Cdc37 chaperone machinery can promote conformational instability of the client kinases through a mechanism of reciprocal dynamic exchange at the binding interfaces, in which protection of the partially unfolded kinase by Hsp90 may spatially confine client ensemble and accelerate refolding.   Network modelling characterized conformational landscapes of a wide range of protein kinases,  revealing that chaperone dependency  of protein kinase clients may be linked with the  elevated conformational mobility of their inactive states induced by  dynamic and energetic polarization of  kinase lobes. By showcasing a family of  cyclin-dependent (CDK) kinases  that display    a broad repertoire  of chaperone dependencies, we discovered that  unique functional dynamics  signatures and chaperone addiction   of CDK4 and CDK7 client proteins  can explain  divergences in their regulatory mechanisms that  require  a confluence of events,  including formation of the inhibitory ternary complex, substrate recruitment and activation loop phosphorylation. We have analyzed mechanisms by which kinase inhibitors and allosteric Hsp90 modulators that may act synergistically and exert their pharmacological effect by depriving the client kinase of access to the molecular chaperone.  Our study offers a systems-based perspective on drug design by unravelling relationships between protein kinase networks with molecular chaperones and binding specificity of targeted kinase drugs. We discuss how these approaches can exploit advances in chemical biology and network science to develop strategies for designing robust combinations of targeted kinase inhibitors and allosteric modulators.

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Ubiquitin Research and Drug Discovery
Novel Drug Targets in the Ubiquitin System
Moderator: Matthew Petroski, Sanford-Burnham Medical Research Institute
10:45
Small Molecule Targeting of SCFFbw7 to Develop Therapeutics for Neurodegenerative Disorders
 
Steven Reed
Steven I. Reed
Professor, Cell and Molecular Biology
The Scripps Research Institute
About Speaker: Steven Reed, Ph.D. is Professor of Cell and Molecular Biology at the Scripps Research Institute in La Jolla. He received an undergraduate degree in Molecular Biophysics and Biochemistry from Yale University and a Ph.D. in Biochemistry from Stanford U... Read Full Bio 
 
 
Steven Reed
Steven I. Reed
Professor, Cell and Molecular Biology
The Scripps Research Institute
 
About Speaker:

Steven Reed, Ph.D. is Professor of Cell and Molecular Biology at the Scripps Research Institute in La Jolla. He received an undergraduate degree in Molecular Biophysics and Biochemistry from Yale University and a Ph.D. in Biochemistry from Stanford University. Dr. Reed carried out postdoctoral research with Nobel laureate Leland Hartwell at the University of Washington and held a faculty position at the University of California, Santa Barbara prior to assuming his current position. He is known for his pioneering work on the roles and regulation of cyclin-dependent kinases in cell cycle control and oncogenesis. More recently he and his wife, Susanna Ekholm-Reed, discovered a novel pathway linking the ubiquitin ligase parkin directly to neuronal survival, leading to identification of a potential therapeutic target for treating Parkinson’s disease. Dr. Reed is a founder of NeuroMantis Pharmaceuticals, a company dedicated to developing therapeutics targeting neuronal cell death in neurodegenerative disease and other pathological conditions.

 
Abstract: Parkinson’s disease (PD) is cha...Read More 

Parkinson’s disease (PD) is characterized by a spectrum of motor disorders that is caused be progressive death of dopaminergic neurons in a midbrain region known as the substantia nigra pars compacta (SNpc). Although 60,000 new cases of PD present in the US every year and an estimated 10 million people are living with the disease world-wide, there is no known effective treatment and the disease is invariably progressive. Although most PD is sporadic in nature, a significant cohort has been shown to be transmitted genetically. By investigating the genes and mutations that cause PD, it has been hoped that an understanding of the etiology and pathology of the disease at the molecular level will lead to effective therapies. In that vein, we have been engaged in research aimed at understanding the role of parkin, a ubiquitin ligase encoded by the most frequently mutated gene in recessive hereditary PD, PARK2. Our research has led to the conclusion that the neuroprotective effect of parkin is mediated, at least in part, by targeting the substrate binding adaptor of another ubiquitin ligase, SCFFbw7, for ubiquitin-mediated proteasomal degradation. We have also determined that the critical targets of the SCFFbw7 ubiquitin ligase in this context are the pro-survival Bcl-2 family member Mcl-1, essential for neuronal survival, and PGC-1α, a transcriptional co-activator important for mitochondrial biogenesis and homeostasis. Using an in silico approach, we have identified small molecule inhibitors of SCFFbw7. All bind to Fbw7 and prevent it from targeting Mcl-1 and PGC-1α in mouse primary neurons and in brains. Most importantly, these compounds protect primary neurons from various forms of stress-induced apoptosis at subnanomolar concentrations. Therefore, to validate Fbw7 as a therapeutic target in vivo, we chose an inhibitor with good pharmacokinetic properties, 20aS20, and tested it on three diverse murine PD models: the MPTP intoxication model, the stereotaxic injection of recombinant aav expressing α-synuclein, and the MitoPark mouse, a chronic genetic model that causes loss of mtDNA in dopaminergic neurons and therefore progressive neuron loss. In each case, treatment with 20aS20 reduced nigral TH+ neuron loss associated with the model. In the case of the MitoPark model, consistent with mitigation of TH+ neuron loss, motor and behavioral phenotypes were significantly suppressed. Therefore, inhibition of SCFFbw7 shows promise as a concept for developing PD therapeutics. We are currently carrying out lead optimization to develop candidates for clinical trials.

 

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11:10
Signaling in the Catalytic Subunit of Protein Kinase A via Hydrophobic Motifs
 
Gianluigi  Veglia
Gianluigi Veglia
Professor, Biochemistry, Molecular Biology, and Biophysics
University of Minnesota
About Speaker: Gianluigi Veglia received his master degree in Chemistry from the University of Rome, La Sapienza, with a thesis on the “Synthesis and NMR Characterization of New b-Carboline Derivatives” under the direction of Profs. M. R. Del Giudice and M. Del... Read Full Bio 
 
 
Gianluigi  Veglia
Gianluigi Veglia
Professor, Biochemistry, Molecular Biology, and Biophysics
University of Minnesota
 
About Speaker:

Gianluigi Veglia received his master degree in Chemistry from the University of Rome, La Sapienza, with a thesis on the “Synthesis and NMR Characterization of New b-Carboline Derivatives” under the direction of Profs. M. R. Del Giudice and M. Delfini.  In 2004, under the supervision of Prof. M. Delfini at the University of Rome, La Sapienza, he received a Ph.D. degree in Physical Chemistry, with a thesis on “Macromolecular Interactions by NMR Spectroscopy”. He also collaborated with Prof. A. Di Nola focusing on the characterization of conformational motions in small polypeptides using molecular dynamics simulations techniques. For several years, Dr. Veglia was a postdoctoral associate in the laboratory of Prof. S. Opella in the Department of Chemistry at the University of Pennsylvania, where he optimized solution NMR methods for the structure determination of membrane proteins. In 2000, he joined the Department of Chemistry at the University of Minnesota as an Assistant Professor, where he focused on the structural and dynamic characterization of soluble and membrane-bound proteins involved in skeletal and cardiac muscle contractility. In 2006, he was promoted to Associate Professor with a joint appointment between the Department of Chemistry and the Department of Biochemistry, Molecular Biology & Biophysics. In 2009, Dr. Veglia was promoted to full Professor. Currently, Dr. Veglia uses an interdisciplinary approach to correlate the structure and dynamics of integral and peripheral membrane proteins with their biological function. Specifically, he combines biochemical assays with solution and solid-state NMR, and computational methods to place the high-resolution structures and conformational dynamics of proteins and protein complexes in the context of their biological function and disease associations. More details about Dr. Veglia’s research projects can be found at http://veglia.chem.umn.edu/.

 
Abstract: ...Read More 

Eukaryotic protein kinases (EPKs) constitute a class of allosteric switches that mediate several signaling events. Protein kinase A is a prototypical kinase of paramount biological importance as it is involved in a myriad of cellular processes. Using side-chain methyl group NMR relaxation measurements, we traced the allosteric signaling through the hydrophobic spines of the enzyme in the apo, binary (nucleotide bound) complex and ternary (nucleotide and pseudo-substrate bound) forms. In the apo form, the C-spine is disassembled, with the two lobes of the enzyme dynamically uncommitted. Nucleotide binding locks the architecture of the catalytic spine, synchronizing the motions (committed dynamics) in the hydrophobic core. While pseudo-substrate binding further rigidifies of the spines, the conformational dynamics of the core are retained with natural substrates. Since the C-subunit is highly conserved within the kinase family, the present study offers novel mechanistic insights into intramolecular signaling of protein kinases that can serve for the design of novel activators or inhibitors of kinases. 

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11:10
Using IMiD-derivatives and ProTaCs to Induce the Proteolysis of Target Proteins by Cereblon
 
Rusty Lipford
Rusty Lipford
Principal Scientist
Amgen
About Speaker: - PhD at MIT with Steve Bell (1996-2000) - Postdoctoral studies with Ray Deshaies at Caltech (2001 -2005) - Amgen Oncology Discover Research (2006 - present) (Scientist 2006 - 2009) (Senior Scientist 2009 - 2012) (Principal Scientist (2012 - present)... Read Full Bio 
 
 
Rusty Lipford
Rusty Lipford
Principal Scientist
Amgen
 
About Speaker:

- PhD at MIT with Steve Bell (1996-2000) - Postdoctoral studies with Ray Deshaies at Caltech (2001 -2005) - Amgen Oncology Discover Research (2006 - present) (Scientist 2006 - 2009) (Senior Scientist 2009 - 2012) (Principal Scientist (2012 - present)

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11:35
Innovative Technologies Packages for Kinase Drugs with Diverse Inhibition Modes
 
Lars Neumann
Lars Neumann
Assays, Biophysics & Screening
Proteros Biostructures
About Speaker: 2008-current: Head of Assays, Biophysics & Screening at Proteros Biostructures 2005-2008: Group Leader Assay Development & Screening at GPC Biotech 2002-2005: Senior Scientist Assay Development & Screening at Axxima Pharmaceuticals 2000-2... Read Full Bio 
 
 
Lars Neumann
Lars Neumann
Assays, Biophysics & Screening
Proteros Biostructures
 
About Speaker:

2008-current: Head of Assays, Biophysics & Screening at Proteros Biostructures 2005-2008: Group Leader Assay Development & Screening at GPC Biotech 2002-2005: Senior Scientist Assay Development & Screening at Axxima Pharmaceuticals 2000-2005: Postdoc at Stanford University in the laboratory of Brian Kobilka (biophysics on GPCRs) 1996-2000: Ph.D. thesis at Max-Planck Institute for Biochemistry 1991-1996: Programm of Chemistry and Biochemistry at the University of Munich.

 
Abstract: Since nearly two decades kinases are ...Read More 

Since nearly two decades kinases are attractive drug targets. While initially mainly the ATP site was addressed by developing ATP competitive inhibitors,, in the recent years more and more alternative modes of inhibitionsare utilized to overcome the typical kinase inhibitor challenges such as selectivity, efficacy and resistance formation. Less conserved kinase-interaction sites are addressed by allosteric inhibitors, that are independent from the high cellular ATP concentration. Kinase activity is inhibited by protein-protein-interaction inhibitors, that block complex formation of kinases with associated functional proteins. Inhibitor residence time on the kinase in combination with kinetic selectivity became an important optimization parameter.IInhibitors selective for distinct activation states of kinases are engineered. Covalent inhibitors are designed attacking defined residues within the kinase. These developments require a fundamental change in the tools and technologies that support kinase drug discovery. Proteros biostructures has established technology packages that combine biochemistry with innovative biophysics and protein crystallography to allow efficient and data driven generation of such novel kinase inhibitors. The Proteros platform enables to screen specifically for allosteric inhibitors. Assays are established to identify compounds blocking kinase relevant protein-protein interactions. High throughput kinetic profiling provides knowledge about binding affinity and at the same time binding kinetics against on- and off-kinase targets for all compounds synthesized in a program to facilitate rapid generation of residence time optimized inhibitors. High throughput binding assays allow to screen for inhibitors addressing non-activated kinases states. Methods are in place that de-convolute the binding of covalent inhibitors into the non-covalent and the covalent contribution to escape resistance formation. Protein crystallography discloses different binding modes and enables medicinal chemistry to improve inhibitor properties. The presentation demonstrates the application and the interplay of these different technologies for an efficient drug discovery process towards innovative kinase inhibitors exemplified for several challenging kinase targets as among others the mTOR complex.

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11:35
Cytosolic Iron-sulfur Assembly is Evolutionarily Tuned by a Cancer-amplified Ubiquitin Ligase
 
Ryan Potts
Ryan Potts
Associate Member, Cell & Molecular Biology Department
St. Jude Children's Research Hospital
About Speaker: Ryan Potts obtained his B.S. in Biology from the University of North Carolina at Chapel Hill in 2000, and his Ph.D. in Cell Regulation from the UT Southwestern Medical Center in 2007. He then did his postdoctoral research at UT Southwestern Medical C... Read Full Bio 
 
 
Ryan Potts
Ryan Potts
Associate Member, Cell & Molecular Biology Department
St. Jude Children's Research Hospital
 
About Speaker:

Ryan Potts obtained his B.S. in Biology from the University of North Carolina at Chapel Hill in 2000, and his Ph.D. in Cell Regulation from the UT Southwestern Medical Center in 2007. He then did his postdoctoral research at UT Southwestern Medical Center in the Department of Biochemistry as a Sara and Frank McKnight Independent Postdoctoral Fellow (2008-2011). In September 2011, Dr. Potts joined the Department of Physiology at UT Southwestern Medical Center as a tenure-track Assistant Professor. In January 2016, he moved to St. Jude Children’s Research Hospital as Associate Professor in the department of Cell and Molecular Biology. His scientific interest is in delineating the functions of the MAGE family of E3 ubiquitin ligase regulators.

 
Abstract: The cytosolic iron-sulfur (Fe-S) clus...Read More 

The cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway functions to incorporate inorganic Fe-S cofactors into a variety of proteins, including several DNA repair enzymes. However, the mechanisms regulating the CIA pathway are unknown. We describe here that the MAGE-F1-NSE1 E3 ubiquitin ligase regulates the CIA pathway through ubiquitination and degradation of the CIA targeting protein MMS19. Over-expression or knock out of MAGE-F1 altered Fe-S incorporation into MMS19-dependent DNA repair enzymes, DNA repair capacity, sensitivity to DNA damaging agents, and iron homeostasis. Intriguingly, MAGE-F1 has undergone adaptive pseudogenization in select mammalian lineages.  In contrast, MAGE-F1 is highly amplified in multiple human cancer types and amplified tumors have increased mutational burden. Thus, flux through the CIA pathway can be regulated by degradation of the substrate-specifying MMS19 protein and its downregulation is a common feature in cancer and is evolutionarily controlled.

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12:00
Application of Next Generation Modeling to Novel Kinases
 
Jose Duca
Jose Duca
Head, Computer-Aided Drug Discovery
Novartis
About Speaker: José is Global Head of Computer Aided Drug Discovery (CADD), part of Global Discovery Chemistry at the Novartis Institutes for BioMedical Research (NIBR). José joined Novartis in 2010. Previously, he had been with the Schering-Plough Research Inst... Read Full Bio 
 
 
Jose Duca
Jose Duca
Head, Computer-Aided Drug Discovery
Novartis
 
About Speaker:

José is Global Head of Computer Aided Drug Discovery (CADD), part of Global Discovery Chemistry at the Novartis Institutes for BioMedical Research (NIBR).

José joined Novartis in 2010. Previously, he had been with the Schering-Plough Research Institute and Merck Research Laboratories in Kenilworth, NJ, USA for 10 years where he had increasing responsibilities in the CADD group. His scientific fields of expertise within computational chemistry comprise molecular thinking, modeling, ab initio calculations, molecular recognition, QM-MM methods, solvation and structure-based drug design. José is passionate about drug discovery.

He received his Ph.D. in Chemistry from the National University of Córdoba, Argentina. He joined Prof. Tony Hopfinger’s group in the College of Pharmacy at the University of Illinois at Chicago as a Postdoctoral Fellow.

 
Abstract: We created a new paradigm to explore ...Read More 

We created a new paradigm to explore two of the most relevant themes in drug discovery: the structure-energy and the in vitro-in vivo relationships. Our approaches rely on first principles and suggest we need to re-think structure-based drug design and its application to drug discovery. The talk will exemplify several aspects of this new approach and its application to real-world examples within the field of kinases (MELK, WNK, CDK2).

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12:00
Chemical libraries to unlock deubiquitylase (DUB) targeted drug discovery
 
Jason Brown
Jason Brown
Scientific Director
Ubiquigent
About Speaker: Jason co-founded Ubiquigent in 2009 in collaboration with the University of Dundee, the Medical Research Council and Stemgent Inc.  Before starting Ubiquigent he was part of a biotech investment and operations group and involved in supporting a mole... Read Full Bio 
 
 
Jason Brown
Jason Brown
Scientific Director
Ubiquigent
 
About Speaker:

Jason co-founded Ubiquigent in 2009 in collaboration with the University of Dundee, the Medical Research Council and Stemgent Inc.  Before starting Ubiquigent he was part of a biotech investment and operations group and involved in supporting a molecular diagnostics, kinase drug discovery and various other drug discovery-focused service companies as well as evaluating investment opportunities. Prior to this he built and ran a kinase-focused assay development and drug discovery service facility for Upstate Biotechnology, a leading provider of cell signalling research products and services.  Jason received his MPhil and DPhil from the University of Cambridge in association with Parke-Davis/Warner-Lambert (Pfizer), during which he identified a voltage-dependent calcium channel subunit as the molecular target of the blockbuster epilepsy and neuropathic pain drugs Neurontin and Lyrica.  After his DPhil Jason worked in and subsequently ran an assay development group for Parke-Davis.

Ubiquigent provides access to the necessary expertise, chemistry (recently launching DUBtarget™-001, a deubiquitylase targeted hit-finding library), high quality research tools and integrated and collaborative drug discovery services required to support its commercial and academic partners in pursuing ubiquitin system-focused drug discovery programmes, and in undertaking basic research.

 
Abstract: Ubiquigent is a world leading provide...Read More 

Ubiquigent is a world leading provider of ubiquitin system targeted drug discovery tools and services.  Within the ubiquitin signalling cascade the deubiquitylase (DUB) enzyme family offers a deep seam of drug target opportunities addressing an array of therapeutic areas.  A number of recent publications have reported significant progress with the development of high affinity and highly selective small molecule DUB inhibitors demonstrating that this emerging target class is chemically tractable.  We will discuss Ubiquigent’s commercially accessible first-in-class novel DUB targeted hit-finding chemical library DUBtarget™-001 and its characterisation employing our integrated service platforms featuring the DUBprofiler™ screening and selectivity and REDOXprofiler™ hit triage capabilities.

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12:25
Lunch Provided by GTCbio
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Protein Kinases in Drug Discovery
Kinome Selectivity and Clinical Translation
Moderator: Gennady Verkhivker, Chapman University
2:10
Kinase as targets: Quo vadis ?
 
Doriano Fabbro
Doriano Fabbro
CSO
PIQUR Therapeutics
About Speaker: Doriano Fabbro, Chief Scientific Officer of PIQUR Therapeutics AG, received his Ph.D. in cell biology and biochemistry at the University of Basel, where he worked afterwards for 12 years as Group Leader in Molecular Tumor Biology. In 1991, he joined ... Read Full Bio 
 
 
Doriano Fabbro
Doriano Fabbro
CSO
PIQUR Therapeutics
 
About Speaker:

Doriano Fabbro, Chief Scientific Officer of PIQUR Therapeutics AG, received his Ph.D. in cell biology and biochemistry at the University of Basel, where he worked afterwards for 12 years as Group Leader in Molecular Tumor Biology. In 1991, he joined the Oncology Group of Ciba-Geigy Basel. After the merger of Ciba-Geigy with Sandoz in 1996 he served at Novartis as Head of Kinase Biology until 2012. Doriano has contributed to the discovery and development of various protein kinase inhibitors for the treatment of cancer; e.g. Midostaurin®, Glivec®, Afinitor®, and Tasigna®. Doriano is author in more than 200 publications and numerous patents in the area of protein kinases regulation, structure, screening and drug discovery. He has been honored with the Novartis Oncology President’s Award (2005).

 
Abstract: To date 42 small molecular weight kin...Read More 

To date 42 small molecular weight kinase inhibitors (SMWKIs) and a handful of therapeutic antibodies targeting kinases have been approved. The SMWKIs are predominantly multi-targeted and have been approved mainly for treatment of cancer, although deregulation of kinase function has been demonstrated to play an important role in non-oncological indications. The majority of kinases have been historically understudied, indicating that the field of kinase inhibitor discovery is still relatively immature. The challenges for kinase drug discovery development are; understanding the structural basis of SMWKIs selectivity to reduce off-target mediated toxicity efficient compound screening and profiling technologies, overcoming drug resistance validation of novel kinase targets and the utilization of SMWKIs in non-oncological areas.

In my presentation, I will review some of the challenges that the kinase drug discovery field is facing.  

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Ubiquitin Research and Drug Discovery
Advances in Ubiquitin-like Modifications
Moderator: Ryan Potts, St. Jude Children's Research Hospital
2:10
Streptonigrin Inhibits SENP1 and Induces Degradation of Hypoxia-inducible Factor 1α (HIF1α)
 
Yuan Chen
Yuan Chen
Professor of Molecular Medicine
Beckman Research Institute of the City of Hope
About Speaker: Yuan Chen, Ph.D., is currently Professor in the Department of Molecular Medicine at the Beckman Research Institute of the City of Hope. She obtained B.S. in Chemistry from the University of Science and Technology of China, and Ph.D. in Biochemistry f... Read Full Bio 
 
 
Yuan Chen
Yuan Chen
Professor of Molecular Medicine
Beckman Research Institute of the City of Hope
 
About Speaker:

Yuan Chen, Ph.D., is currently Professor in the Department of Molecular Medicine at the Beckman Research Institute of the City of Hope. She obtained B.S. in Chemistry from the University of Science and Technology of China, and Ph.D. in Biochemistry from Rutgers University. After postdoctoral studies at the Scripps Research Institute, she joined Beckman Research Institute of the City of Hope as tenure-track faculty in 1994. Her laboratory has made major contributions in elucidating the mechanism and regulation of the SUMOylation enzymes and discovered the SUMO-interacting motif that mediates most SUMO-dependent cellular functions. Her current research interests center on the mechanism and inhibition of enzymes in ubiquitin-like modifications and the role of ubiquitin-like modifications in major oncogenesis pathways.

 
Abstract: Streptonigrin (CAS no. 3930-19-6) is ...Read More 

Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have anti tumor activities in clinical trials conducted in the 1960s–1970s. However, its use in clinical studies subsequently faded, due to lack of uniform anti-cancer activity, and the molecular mechanisms of streptonigrin anti-tumor effects remain poorly defined. Here, we show that streptonigrin selectively binds and inhibits the SUMO-specific protease SENP1. NMR studies identified that streptonigrin binds to SENP1 on the surface where SUMO binds and disrupts SENP1-SUMO1 interaction. Treatment of cells with streptonigrin resulted in increased global SUMOylation levels and induced degradation of hypoxia inducible factor alpha (HIF1α, which is critical to angiogenesis in tumors in tumor growth. These findings provide new mechanistic insights into the anti-tumor effects of streptonigrin and inform its modification to improve its efficacy and reduce toxicity for future clinical use.

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2:35
Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor
 
Alexandra  Newton
Alexandra Newton
Distinguished Professor of Pharmacology
UC San Diego
About Speaker: Dr. Alexandra Newton received her Ph.D. in Chemistry from Stanford University in working on membrane biochemistry. She then spent 2 years doing postdoctoral research in Daniel E. Koshland's laboratory at the University of California, Berkeley where s... Read Full Bio 
 
 
Alexandra  Newton
Alexandra Newton
Distinguished Professor of Pharmacology
UC San Diego
 
About Speaker:

Dr. Alexandra Newton received her Ph.D. in Chemistry from Stanford University in working on membrane biochemistry. She then spent 2 years doing postdoctoral research in Daniel E. Koshland's laboratory at the University of California, Berkeley where she was first introduced to protein kinase C. She was on the faculty in the Chemistry Department at Indiana University, before joining the Department of Pharmacology at the University of California, San Diego, where she is now Distinguished Professor of Pharmacology. Her research investigates the cell signaling mechanisms involving protein kinase C and the phosphatase PHLPP.

 
Abstract: Protein kinase C (PKC) isozymes trans...Read More 

Protein kinase C (PKC) isozymes transduce the myriad of signals resulting from receptor-mediated hydrolysis of phospholipids, playing critical roles in diverse cellular functions. The discovery in the 1980s that PKC isozymes are receptors for the potent tumor promoting phorbol esters led to the dogma that activation of PKC by phorbol esters promotes tumorigenesis. Yet three decades of clinical trials using PKC inhibitors in cancer therapies not only failed, but in some cases worsened patient outcome. Why has targeting PKC in cancer eluded successful therapies? Our studies looking at the disease for insight provide an explanation: cancer-associated mutations in PKC are generally loss-of-function, supporting an unexpected function as tumor suppressors. In contrast, activity-enhancing mutations are observed in degenerative disease: germline mutations that enhance the activity of some PKC isozymes are associated with diseases such as Alzheimer’s disease. Our finding that loss-of-function mutations in PKC are associated with cancer and gain-of-function mutations are associated with degenerative disease indicate a paradigm reversal by which therapies to restore PKC function should be used in cancer, and ones to inhibit PKC function may be beneficial for degenerative diseases such as Alzheimer’s Disease.

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2:35
Targeting XIAP in NOD2 Mediated Inflammatory Diseases
 
Domagoj Vucic
Domagoj Vucic
Principal Scientist, Early Discovery Biochemistry
Genentech
About Speaker: Domagoj Vucic, PhD, is a Principal Scientist at Genentech in South San Francisco, USA. He obtained B.S. from the University of Zagreb, Croatia, and Ph.D. from the University of Georgia, USA. He completed postdoctoral training in the laboratory of Dr.... Read Full Bio 
 
 
Domagoj Vucic
Domagoj Vucic
Principal Scientist, Early Discovery Biochemistry
Genentech
 
About Speaker:

Domagoj Vucic, PhD, is a Principal Scientist at Genentech in South San Francisco, USA. He obtained B.S. from the University of Zagreb, Croatia, and Ph.D. from the University of Georgia, USA. He completed postdoctoral training in the laboratory of Dr. Vishva Dixit. Domagoj’s laboratory investigates the biological role of modulators of signaling pathways mediated by ubiquitination, and their involvement in cellular processes triggered by TNF family ligands and other pro-inflammatory stimuli. At Genentech, he leads an effort to develop compounds for blocking uncontrolled inflammatory responses and/or enhancement of the survival of damaged cells and tissues.

 
Abstract: The regulated modification and degrad...Read More 

The regulated modification and degradation of cellular proteins by the ubiquitin-proteasome system are critical for modulation of many essential cellular processes. Ubiquitination has a seminal role in the regulation of the immune system by controlling the stability of cell death modulators and the activation of NF-kB and MAPK signaling pathways. XIAP is a potent caspase inhibitor as well as ubiquitin ligase that is critical for proper NOD2 mediated signaling. We have investigated the spatial and temporal pattern of endogenous ubiquitination and phosphorylation during NOD2 signaling triggered by bacterial products. Our mechanistic studies have revealed the intricate inter-dependency of phosphorylation and ubiquitination of RIP2 and their importance for the regulation of NOD2 mediated inflammatory signaling. These dynamic posttranslational events regulate the assembly of NOD2 associated signaling complexes that promote MAPK and NF-kB activation and production of pro-inflammatory cytokines. Selective targeting of XIAP can efficiently block NOD2 signaling and cytokine production in human primary cells and in vivo without compromising viability of treated cells and tissues. Neutralizing XIAP is especially clinically relevant in NOD2-dependent immune disorders such as Blau syndrome, sarciodosis and Crohn’s disease. Collectively, these studies define major events that regulate NOD2 signaling, and validate XIAP as therapeutic target for anti-inflammatory treatments.

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3:00
Harnessing Conformational Dynamics for the Selective Targeting of Aurora A Catalytic and Scaffolding Functions
 
Nicholas Levinson
Nicholas Levinson
Assistant Professor, Department of Pharmacology
University of Minnesota
About Speaker: Dr. Levinson obtained his Ph.D. in 2008 from the University of California, Berkeley, where he studied the structural biology of the tyrosine kinases Abl, Src and Csk. He pursued postdoctoral training at Stanford University in biophysical chemistry an... Read Full Bio 
 
 
Nicholas Levinson
Nicholas Levinson
Assistant Professor, Department of Pharmacology
University of Minnesota
 
About Speaker:

Dr. Levinson obtained his Ph.D. in 2008 from the University of California, Berkeley, where he studied the structural biology of the tyrosine kinases Abl, Src and Csk. He pursued postdoctoral training at Stanford University in biophysical chemistry and worked on the application of vibrational spectroscopy to biological systems. In 2014, Dr. Levinson was appointed Assistant Professor of Pharmacology at the University of Minnesota, Twin Cities. His lab studies the biophysical basis of allosteric regulation in the protein kinases using diverse spectroscopic methods including vibrational and fluorescence spectroscopy and nuclear magnetic resonance.

 
Abstract: ...Read More 

The protein kinase Aurora A (AurA) plays essential roles in centrosome maturation and mitotic spindle assembly, is overexpressed in a variety of cancers, and forms a stabilizing complex with the oncogenic transcription factor N-Myc in neuroblastoma and neuroendocrine prostate cancer. Small molecule conformational modulators of AurA are highly desired for selectively targeting individual cellular pools of the kinase and for disrupting the interaction of AurA with N-Myc. We have developed a new time-resolved fluorescence-based technology for rapidly profiling the effects of inhibitor binding on the conformation of the kinase activation loop. We show that this method can reliably classify inhibitors into DFG-In versus DFG-Out binders, and can dissect the degree to which an inhibitor promotes one conformational state of another. We present the conformational profiles of all existing AurA inhibitors, identify the compound with the strongest energetic preference for the DFG-Out state, and show that this inhibitor is likely to be effective at blocking N-Myc binding and may represent a promising new treatment for NMYC-amplified cancers.

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3:00
Adaptive Responses to p97 Inhibition
 
Matthew Petroski
Matthew Petroski
Associate Professor
Sanford-Burnham Medical Research Institute
About Speaker: Matthew Petroski is an Associate Professor at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, USA. He received his Ph.D. from the University of California, Irvine and did post-doctoral training at Caltech. His research pro... Read Full Bio 
 
 
Matthew Petroski
Matthew Petroski
Associate Professor
Sanford-Burnham Medical Research Institute
 
About Speaker:

Matthew Petroski is an Associate Professor at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, USA. He received his Ph.D. from the University of California, Irvine and did post-doctoral training at Caltech. His research program focuses on ubiquitin and ubiquitin-like protein signaling and their roles in diseases such as cancer.

 
Abstract: P97 is a hexameric ATPase involved in...Read More 

P97 is a hexameric ATPase involved in the processing of ubiquitin-modified proteins often as a pre-requisite for their degradation by the proteasome. Due to its critical functions in protein homeostasis mechanisms such as endoplasmic reticulum-associated degradation (ERAD) and the unfolded protein response (UPR), p97 has emerged as a potential target for cancer therapeutics with potent and selective inhibitors recently described. Through the use of advanced ATP-competitive and allosteric inhibitors on cells with increased mutation rates, we have identified gain of function mutations in p97 that are sufficient to overcome the normally cytotoxic effects of these molecules. In addition to mutations that have inhibitor specific effects, the P472L mutation in the linker between D1 and D2 ATPase domains renders p97 insensitive to both classes of inhibitors. While the mutation affects the binding of an allosteric inhibitor, it does not for an ATP-competitive inhibitor. Biochemical and biophysical experiments indicate that P472L alters ATP and ADP binding to D2 and increases the enzyme’s catalytic efficiency while not affecting D1 activity. Our data support a model where P472L changes the normally tight intra-subunit regulation of p97 where ATP binding to D2 is necessary for D1 activation. In this case, we propose that increased ATP hydrolysis by D2 effectively out-competes ATP competitive inhibitors while maintaining regulated D1 activity to allow for productive p97 functions. Overall, our study provides new evidence of the remarkable adaptability of p97 to fulfill its essential cellular functions.

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3:25
Regulation of Muscle Protein Synthesis and Degradation, Mitochondrial and Sarcomere Structures by the Kinome and Phosphatome in C. Elegans
 
Nate Szewczyk
Nate Szewczyk
Professor, School of Medicine
University of Nottingham
About Speaker: Nathaniel Szewczyk is a Professor of Space Biology at the University of Nottingham. His general research focus is on muscle biology where he uses a combination of cultured cells, C. elegans, rodents, and human volunteers to understand the genetic and... Read Full Bio 
 
 
Nate Szewczyk
Nate Szewczyk
Professor, School of Medicine
University of Nottingham
 
About Speaker:

Nathaniel Szewczyk is a Professor of Space Biology at the University of Nottingham. His general research focus is on muscle biology where he uses a combination of cultured cells, C. elegans, rodents, and human volunteers to understand the genetic and environmental control of muscle homeostasis. His work has been funded by national funders in Japan (JAXA), the UK (UK Space Agency, BBSRC, MRC), and the US (NASA, NIH). He has successfully completed 11 experiments on-board the International Space Station using model systems and is currently studying the molecular basis of, and interventions to prevent, muscle loss with age in both C. elegans and human volunteers. He is an investigator in the Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, the National Centre for Sport and Exercise Medicine, and the National Institute of Health Research Nottingham Biomedical Research Centre. He is in charge of the molecular medicine curriculum for the University of Nottingham’s Graduate Entry Medicine medical degree course, currently serves as a panel member for the Italian Ministry of Health’s Muscle Study Section, and is the chair of the European Space Agency’s Ageing Topical Team.

 
Abstract: Skeletal muscle is central to locomot...Read More 

Skeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, which is relevant to at least one model of neurodegeneration, and nerve signal to muscle to oppose proteasome-based degradation which is relevant to starvation and at least one model of neurodegeneration. In order to expand our knowledge of the regulation of muscle protein degradation by the genome as well as to understand genomic control of mitochondrial and sarcomere structure we undertook several RNAi screens in C. elegans. We specifically targeted >90% of protein kinases and phosphatases In both sets of RNAi knockdowns, disrupted proteostasis is most commonly observed, followed by mitochondrial and then sarcomere structural alterations. These observations suggest that muscle metabolism is more heavily regulated by the genome than sarcomere structure; interestingly mutants previously identified as having altered muscle function more frequently show disruption of both muscle metabolism and structure than do RNAi treatments against individual kinases or phosphatases. In the kinase screen, roughly 40% of kinases were identified as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. In the phosphatase screen, roughly 50% of phosphatases were identified as required to for muscle health; 86 have identified human orthologues and 57 are known to be expressed in human skeletal muscle. In both the screens, of the genes required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy, suggesting autophagy is the most commonly triggered protein degradation in muscle in response to altered gene expression. These screens have identified individual kinases and phosphatases that appear important for the regulation of worm muscle, discoveries that are ripe for translation into human muscle studies.

* C. elegans is a good tool for studying the kinome
* 53 kinases expressed in human muscle regulate C. elegans muscle
* Most kinases required for normal muscle development are also required for maintained muscle health
* More kinases regulate autophagy than other proteolytic systems

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3:25
Reactive-site-centric Chemoproteomics Identifies a Structurally-distinct Class of Deubiquitinase Enzymes
 
David Hewings
David Hewings
Postdoctoral Research Fellow
Genentech
About Speaker: David Hewings received his undergraduate degree in Chemistry and doctorate in Organic Chemistry from the University of Oxford. At Genentech he is developing new chemoproteomic methods to study deubiquitinase activity, in collaboration with Stanford U... Read Full Bio 
 
 
David Hewings
David Hewings
Postdoctoral Research Fellow
Genentech
 
About Speaker:

David Hewings received his undergraduate degree in Chemistry and doctorate in Organic Chemistry from the University of Oxford. At Genentech he is developing new chemoproteomic methods to study deubiquitinase activity, in collaboration with Stanford University.

 
Abstract: Activity-based probes (ABPs) are wide...Read More 

Activity-based probes (ABPs) are widely used to monitor the activity of enzyme families in biological systems. Inferring enzymatic activity from probe reactivity requires that the probe reacts with the enzyme at its active site; however, this is rarely verified since the sites of probe labeling are not determined. Here we present an enhanced chemoproteomic approach to study the activity of deubiquitinase enzymes. We designed bioorthogonally-tagged deubiquitinase ABPs and developed a sequential on-bead digestion protocol to enhance the identification of probe labeling sites. We confirmed probe labeling of deubiquitinase catalytic cysteine residues and reveal unexpected labeling of non-catalytic cysteine residues across deubiquitinase classes and of non-deubiquitinase proteins. Furthermore we identified a previously-unannotated deubiquitinase with high selectivity towards K63-linked chains and no homology with other deubiquitinase classes. This reactive-site-centric chemoproteomics method is broadly applicable for identifying the reaction sites of covalent molecules on proteins, which may contribute to understanding new enzymatic mechanisms.

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3:50
Afternoon Networking Break
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Round Table Discussions

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5:25
Networking Reception & Poster Session
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Day - 2 Friday, February 23, 2018
 
7:15
Breakfast with Mentors from Academia and Industry (RSVP Only)
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7:30
Continental Breakfast
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Epigenetic Enzymes in Drug Discovery
Epigenetic Modification and Transcriptional Regulation
Moderator: Tamara Maes, Oryzon
8:30
Genome-Wide Screen for Modifiers of Progranulin Reveal Potential Therapeutic Targets for Dementia
 
Steve  Finkbeiner
Steve Finkbeiner
Director, Center for Neurodegenerative Disease; Professor, Neurology and Physiology
Gladstone Institute of Neurological Disease; University of California, San Francisco
About Speaker: Dr. Finkbeiner studies the molecular mechanisms relating to the pathogenesis of neurodegenerative diseases focusing on the role of protein dyshomeostasis in Huntington's disease, Parkinson's disease, ALS, and Frontotemporal dementia. In this context,... Read Full Bio 
 
 
Steve  Finkbeiner
Steve Finkbeiner
Director, Center for Neurodegenerative Disease; Professor, Neurology and Physiology
Gladstone Institute of Neurological Disease; University of California, San Francisco
 
About Speaker: Dr. Finkbeiner studies the molecular mechanisms relating to the pathogenesis of neurodegenerative diseases focusing on the role of protein dyshomeostasis in Huntington's disease, Parkinson's disease, ALS, and Frontotemporal dementia. In this context, he has developed a robotic microscopy, a fully automated high throughput single cell analysis platform that provides very sensitive measures of phenotypes, which has been used to discover disease-related phenotypes in differentiated neurons from patients with neurodegenerative diseases. Dr. Finkbeiner earned concurrently an MD and a PhD from Yale University, followed by an internship and chief residency at the University of California, San Francisco, and a research fellowship at Harvard Medical School.
 
Abstract: Progranulin haploinsufficiency causes...Read More 

Progranulin haploinsufficiency causes frontotemporal dementia, and polymorphisms in the progranulin gene are associated with Alzheimer’s disease and other neurodegenerative diseases. To better understand how progranulin is regulated, we performed a genome-wide genetic screen to discover modifiers that govern progranulin production. Nearly half of the modifiers are involved in transcription including some that are known epigenetic modulators. Other modifiers fell into pathways involved in protein homeostasis and inflammation. Tool compounds existed for several of the modifiers including an epigenetic target from the druggable part of the genome. The compounds replicated the effect of genetic inhibition, inducing progranulin in a dose-dependent manner, some at nanomolar concentrations. Interestingly, progranulin deficiency leads to abnormality in lysosome structure and function, which may be important for its link to neurodegeneration and can be reversed by the modifiers found. This presentation will benefit the audience by (1) providing an update on targets for neurodegenerative disease, (2) suggesting a novel hypothesis by which progranulin may regulate the risk of neurodegeneration broadly, (3) revealing novel targets that regulate progranulin including epigenetic modifiers and (4) showing that hits from these genetic screens can be readily drugged to have similar effects.

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Protease Inhibitors in Drug Discovery
Chemistry and Drug Design for Protease Inhibitors
Moderator: Julio Camarero, USC School of Pharmacy
8:30
Using the Cyclotide Scaffold to Target Protein-protein Interactions
 
Julio A. Camarero
Julio A. Camarero
Professor, Pharmacology and Pharmaceutical Sciences
University of Southern California School of Pharmacy
About Speaker: Professor Camarero started his studies in chemistry at the University if Barcelona (Spain), received his Master degree in 1992, and finished his PhD thesis there in 1996. Afterwards he joined the group of Prof. Tom W. Muir at The Rockefeller Universi... Read Full Bio 
 
 
Julio A. Camarero
Julio A. Camarero
Professor, Pharmacology and Pharmaceutical Sciences
University of Southern California School of Pharmacy
 
About Speaker:

Professor Camarero started his studies in chemistry at the University if Barcelona (Spain), received his Master degree in 1992, and finished his PhD thesis there in 1996. Afterwards he joined the group of Prof. Tom W. Muir at The Rockefeller University as a Burroughs Wellcome Fellow where he contributed to the development of new chemoselective ligation techniques for the chemical engineering of proteins. In 2000, he moved to the Lawrence Livermore National Laboratory as a Distinguished Lawrence Fellow where he became staff scientist and head of laboratory in 2003. He joined the University of Southern California in 2008 as an Associate Professor, becoming Full Professor in 2015. His current research interests are focused in the development of new bioorganic approaches using protein splicing and synthetic protein chemistry for studying biological processes involved in cancer and how can be modulated or inhibited by novel microprotein scaffolds. Professor Camarero has authored over 90 peer-reviewed publications and five invited book chapters.

 
Abstract: We report novel methods for the biosy...Read More 

We report novel methods for the biosynthesis of natively-folded MCoTI-based cyclotides inside live E. coli cells using a split protein splicing units. The cyclotide MCoTI-cylotides are potent trypsin inhibitors recently isolated from the seeds of Momordica cochinchinensis, a plant member of cucurbitaceae family. Biosynthesis of genetically encoded cyclotide-based libraries opens the possibility of using single cells as microfactories where the biosynthesis and screening of a particular inhibitor can take place in a single process within the same cellular cytoplasm. The cyclotide scaffold has a tremendous potential for the development of therapeutic leads based on their extraordinary stability and potential for grafting applications. We will show an example, where a large cyclotide-based genetically-encoded library was used to screen for low nanomolar antagonists for the Hdm2-HdmX RING-mediated E3 ligase activity. We will also present different strategies to improve the cellular uptake and pharmacokinetic profiles of bioactive cyclotides.

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8:55
Microscopic Imaging of Epigenetic Landscapes - Novel Platform for Epigenetic Drug Discovery
 
Alexey  Terskikh
Alexey Terskikh
CSO; Associate Professor, Development, Aging and Regeneration Program
Stelvio Therapeutics; Sanford Burnham Prebys Medical Discovery Institute
About Speaker: Alexey Terskikh earned his Ph.D. at the University of Lausanne, Switzerland in 1996, in the laboratory of Prof. J.P. Mach, where he designed a new type of high-avidity recombinant molecule called Peptabody. He received postdoctoral training with Prof... Read Full Bio 
 
 
Alexey  Terskikh
Alexey Terskikh
CSO; Associate Professor, Development, Aging and Regeneration Program
Stelvio Therapeutics; Sanford Burnham Prebys Medical Discovery Institute
 
About Speaker:

Alexey Terskikh earned his Ph.D. at the University of Lausanne, Switzerland in 1996, in the laboratory of Prof. J.P. Mach, where he designed a new type of high-avidity recombinant molecule called Peptabody. He received postdoctoral training with Prof. Irving Weissman at Stanford University, where he discovered a common genetic program between hematopoietic and neural stem cells. Dr. Terskikh holds an Assistant Professor position in the Brain and Mind Institute at EPFL in Lausanne, Switzerland (2002-2006) and was recruited to SBP as Adjunct Assistant Professor in 2002 and as a full time Assistant Professor in 2006. Dr. Terskikh was promoted to Associate Professor in 2012. His lab is currently focused on molecular mechanisms of self-renewal and differentiation of neural stem cells in normal neurogenesis and in brain tumors and develops novel tools for epigenetic analysis at a single cell level.

8:55
Mechanism of Allosteric Activation of Tryptase: Dual Functionality of Tryptase Protomers as Both Proteases and Cofactors
 
Bob  Lazarus
Bob Lazarus
Principal Scientist, Early Discovery Biochemistry
Genentech
About Speaker: Bob Lazarus is a Principal Scientist in the Department of Early Discovery Biochemistry at Genentech, Inc. He joined Genentech in 1983 after receiving his Ph.D. in Chemistry (1979) and carrying out postdoctoral research at Penn State University. He se... Read Full Bio 
 
 
Bob  Lazarus
Bob Lazarus
Principal Scientist, Early Discovery Biochemistry
Genentech
 
About Speaker:

Bob Lazarus is a Principal Scientist in the Department of Early Discovery Biochemistry at Genentech, Inc. He joined Genentech in 1983 after receiving his Ph.D. in Chemistry (1979) and carrying out postdoctoral research at Penn State University. He served as the Secretary and then President of the International Proteolysis Society from 2011-2015. Bob has explored protein engineering and mechanistic enzymology projects to investigate molecular, biochemical and biological aspects of protein/protein and protein/ligand interactions. His research areas have included tryptase inhibitors for asthma, HGF/Met receptor tyrosine kinase signal transduction implicated in tumorigenesis, metastasis and tissue repair, BACE1 inhibitors for Alzheimer’s disease, the Hedgehog pathway of developmental biology and cancer, molecular diversity scaffolds by phage display, improved versions of DNase I with increased enzymatic activity for CF and other diseases, exosite inhibitors of coagulation Factor VIIa as protease inhibitors and anticoagulants, Kunitz domains as scaffolds for protease inhibition, GPIIb-IIIa integrin antagonists from snake venoms and leeches as platelet aggregation inhibitors and microbial pathway engineering for bioconversion of glucose to vitamin C.

 
Abstract: Human β-tryptase, a tetrameric t...Read More 

Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of the allergic inflammatory responses in asthma. During acute hypersensitivity reactions, mast cells degranulate, releasing the active tetramer along with proteoglycans into the extracellular environment.  While there have been efforts to develop specific inhibitors of tryptase, further understanding of its unique mechanism of activation may lead to novel approaches for developing inhibitors for therapeutic intervention. Tryptase is active only after proteolytic removal of the pro-domain followed by formation of a tetramer via two symmetry-related small and large interfaces. Dissociation of the tetramer into monomers is accompanied with loss in enzymatic activity under physiologically relevant conditions. Engineered mutants at the N-terminus that can no longer insert into the activation pocket are also unable to form tetramers, showing allosteric linkage at multiple sites on each protomer. We engineered specific cysteines into each of the two distinct interfaces of the tryptase tetramer such that they can only dissociate into distinct covalent dimers. Using size exclusion chromatography and enzymatic assays, we show that the two large tetramer interfaces regulate enzymatic activity, elucidating the importance of this protein-protein interaction for allosteric regulation. Our protein engineering efforts ultimately resulted in making an active tryptase dimer that is covalently linked at the large interface and does not require heparin for activity. Furthermore, we demonstrate that heparin is an important cofactor for enzymatic activity by controlling the stability of the tetrameric state at the small tetramer interfaces. In addition we show that a monomeric tryptase mutant unable to form a dimer or tetramer under physiological conditions can be active, but only in the presence of heparin at very high concentrations. Thus heparin can act not only to stabilize the tetramer, but also to allosterically condition the active site. We hypothesize that each tryptase protomer in the tetramer has two distinct roles, acting both as a protease and as a cofactor for its neighboring protomer to allosterically regulate enzymatic activity, providing a rationale for direct correlation of tetramer stability with proteolytic activity.

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9:20
The Druggability Studies of Few Histone Modifying Enzymes
 
Haiching Ma
Haiching Ma
Chief Science Officer
Reaction Biology
About Speaker: Dr. Haiching Ma is the Chief Scientific Officer and a Board Director of Reaction Biology Corp. and has played essential roles in developing and commercializing RBC’s drug screening, profiling and early drug discovery technologies. His recent r... Read Full Bio 
 
 
Haiching Ma
Haiching Ma
Chief Science Officer
Reaction Biology
 
About Speaker:

Dr. Haiching Ma is the Chief Scientific Officer and a Board Director of Reaction Biology Corp. and has played essential roles in developing and commercializing RBC’s drug screening, profiling and early drug discovery technologies. His recent research has focused on epigenetic and kinase targets and the development of biological and chemical tools for understanding their biochemical and cellular functions. As Principle Investigator, he has been awarded over $12 million in NIH SBIR and RO1 grants to pursue research projects on drug discovery and probe development for epigenetic, kinase and protease targets, technology development for small molecule and protein microarray platforms and assay development to enable early drug discovery efforts targeting kinases and epigenetic modulators. Dr. Ma currently serves as a national Steering Committee Member for the NIH National Cancer Institute’s Chemical Biology Consortium.

 
Abstract: Reaction Biology is developing method...Read More 

Reaction Biology is developing methodologies and technologies for early drug discovery activities against variety of histone methyltransferases (HMTs). In this presentation, we’ll present few tailored approaches for targeting different HMTs that are typically considered as tough targets for identifying and confirming hit compounds. Assay development and high throughput screening with biochemical and biophysical approaches will be discussed, cell assays to confirm assay hits will be introduced.

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9:20
HTS by NMR of Focused Combinatorial Libraries for the Identification of Potent and Selective Inhibitors of Metallo-Enzymes
 
Maurizio  Pellecchia
Maurizio Pellecchia
Professor of Biomedical Sciences
University of California, Riverside
About Speaker: Dr. Pellecchia is a chemical biologist with a strong background in pharmaceutical chemistry, biophysics and translational medicine. He trained at the University of Naples (Italy) where he obtained a MS in Organic Chemistry and a Ph.D. in Pharmaceutic... Read Full Bio 
 
 
Maurizio  Pellecchia
Maurizio Pellecchia
Professor of Biomedical Sciences
University of California, Riverside
 
About Speaker:

Dr. Pellecchia is a chemical biologist with a strong background in pharmaceutical chemistry, biophysics and translational medicine. He trained at the University of Naples (Italy) where he obtained a MS in Organic Chemistry and a Ph.D. in Pharmaceutical Sciences, at the ETH-Zurich (working with 2002 Nobel Laureate Prof. Dr. Kurt Wüthrich) and the University of Michigan. Prior to his recruitment in 2002 at the Burnham Institute for Medical Research as Associate Professor, he spent a few years in the pharmaceutical industry. He has served on the faculty of the now Sanford Burnham Prebys medical Discovery Institute for 14 years where he also served as the Associate Director for Translational Research for the Institute’s NCI designated Cancer Center.

Since 2015 he is a Professor of Biomedical Sciences at the University of California at Riverside, School of Medicine and I hold the Daniel Hays endowed Chair in Cancer Research. In addition is the Director of the Center for Molecular and Translational Medicine at UCR. His research is at the forefront of academic drug discovery andchemical biology initiatives. His goals are to support target identification and validation studies in oncology, neurodegenerative, and infectious diseases. The laboratory focuses primarily on the development of innovative pharmacological agents and subsequently apply such agents in target validation studies using cellular and animal models, both internally and via collaborations. Central to these activities are the developing and the application of novel methods and strategies to drug discovery and translational medicine.

 
Abstract: We have recently proposed a novel app...Read More 

We have recently proposed a novel approach, termed HTS by NMR to iteratively identify and optimize antagonists from collections of >100,000 peptide mimetics.     The approach seems also particularly effective in the fragment-hit to lead optimization stages, when a positional scanning library is generated from an initial weak binder, common to a class of protein targets, and tested by biophysical methods including not only NMR but also ITC.  We have recently applied this approach to metalloproteinases, deriving first a focused positional scanning (POS) combinatorial library of peptide mimetics (of approximately 100,000 compounds) where each element of the library contained the metal-chelating moiety hydroxamic acid at the C-terminal, and subsequently testing the library using NMR spectroscopy.

I will report on the details of the method and its implementations to derive potent and selective MMP targeting agents with only few iterations.  

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9:45
Discovery and Chemical Biology of Gamma-secretase Modulators for Alzheimer’s Disease
 
Doug Johnson
Doug Johnson
Research Fellow, Chemical Biology
Pfizer
About Speaker: Douglas Johnson is a Research Fellow and Head of Chemical Biology at Pfizer Worldwide Research & Development in Cambridge, MA. During his tenure at Pfizer, he has played significant roles on teams that have advanced several clinical candidates in... Read Full Bio 
 
 
Doug Johnson
Doug Johnson
Research Fellow, Chemical Biology
Pfizer
 
About Speaker:

Douglas Johnson is a Research Fellow and Head of Chemical Biology at Pfizer Worldwide Research & Development in Cambridge, MA. During his tenure at Pfizer, he has played significant roles on teams that have advanced several clinical candidates including palbociclib (PD 0332991), a CDK4/6 inhibitor approved in 2015 for the treatment of breast cancer; PF-00217830, a D2 partial agonist for schizophrenia; PF-04457845, a FAAH inhibitor for the potential treatment of CNS disorders; and PF-06648671, a γ-secretase modulator for Alzheimer’s Disease. In addition, his group is interested in applying chemical biology methods to enable drug discovery projects. His group has used clickable photoaffinity probes to characterize the targets and the mechanism of action of gamma-secretase inhibitors (GSIs) and modulators (GSMs) and the off-target of 1st generation BACE inhibitors responsible for the observed ocular toxicity. Prior to Pfizer, Doug was an NIH postdoctoral fellow at Harvard University in the laboratory of Professor David A. Evans. He obtained his Ph.D. in organic chemistry at The Scripps Research Institute under the guidance of Professor Dale L. Boger and graduated summa cum laude from the University of Minnesota with a BS in chemistry.

 
Abstract: Alzheimer’s disease is a devast...Read More 

Alzheimer’s disease is a devastating neurodegenerative disorder where formation and deposition of neurotoxic oligomers of amyloid β42 (Aβ42) is believed to play a pivotal role. Aβ42 is derived from the amyloid precursor protein (APP) via sequential processing by the β-secretase (BACE) and γ-secretase enzymes. Over the past decade, γ-secretase modulators (GSM) have emerged as promising therapeutic agents for selectively reducing brain levels of the neurotoxic Aβ species, but unlike γ-secretase inhibitors (GSIs), do not inhibit γ-secretase cleavage of other critical substrates. This presentation will describe the medicinal chemistry design strategies that resulted in the GSM clinical candidate PF-06648671. In addition, chemical biology approaches using clickable photoaffinity probes to determine the target of GSMs and GSIs within the γ-secretase complex will be discussed.

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10:10
Morning Networking Break
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Epigenetic Enzymes in Drug Discovery
Novel Therapeutic Targets and Translational Studies
Moderator: Edward Kai-Hua Chow, National University of Singapore
10:40
Quantitative Parabolic Optimization Platform (QPOP) Identifies Novel Therapeutic Targets in Proteasome Inhibitor-Resistant Multiple Myeloma
 
Edward Kai-Hua Chow
Edward Kai-Hua Chow
Professor, Department of Pharmacology
National University of Singapore
About Speaker: Edward Kai-Hua Chow is an Assistant Professor and Principal Investigatort at National University of Singapore (NUS) in the Cancer Science Institute of Singapore and the Department of Pharmacology. He received his B.A. in Molecular and Cellular Biolog... Read Full Bio 
 
 
Edward Kai-Hua Chow
Edward Kai-Hua Chow
Professor, Department of Pharmacology
National University of Singapore
 
About Speaker:

Edward Kai-Hua Chow is an Assistant Professor and Principal Investigatort at National University of Singapore (NUS) in the Cancer Science Institute of Singapore and the Department of Pharmacology. He received his B.A. in Molecular and Cellular Biology from the UC Berkeley and his Ph.D. at UCLA. Prior to joining NUS, Dr. Chow was a Postdoctoral Fellow under the guidance of Prof. J. Michael Bishop at UCSF. His research group is interested in understanding how specific genomic alterations affect cancer progression and how this information can be applied towards engineering-based approaches to improve cancer therapy through combinatorial drug design and nanotechnology-based drug delivery and imaging applications. His group is particularly interested in overcoming drug resistance in haematological malignancies and hepatocellular carcinoma.

 
Abstract: Proteasome inhibitor-based drug combi...Read More 

Proteasome inhibitor-based drug combinations have improved multiple myeloma median survival beyond 5 years. Multiple myeloma, however, remains incurable as patients inevitably relapse and become resistant to proteasome inhibitors, such as bortezomib. Thus, there is a need to identify improved drug combinations that may serve as later lines of treatment against bortezomib-resistant multiple myeloma. Utilizing a quantitative parabolic optimization platform (QPOP), optimal drug combinations against bortezomib-resistant multiple myeloma were identified. QPOP does not rely on molecular mechanism modeling but rather uses experimental data to rationally identify optimal drug combinations. As a result, targetable molecular mechanisms of cancer progression can be identified without any previous assumptions or bias. QPOP revealed that drug resistance in multiple myeloma may involve specific epigenetic changes as identified by top-ranked epigenetic inhibitor containing drug combinations. Inhibition of epigenetic modifiers within the appropriate drug combinations can effectively treat models of bortezomib-resistant multiple myeloma, as well as ex vivo primary multiple myeloma cells from a wide range of patients. QPOP analysis also revealed that optimal drug combinations for other classes of epigenetic inhibitors, such as HDAC inhibitors, change from naïve multiple myeloma to drug-resistant multiple myeloma. Thus, QPOP-based drug combination optimization not only revealed effective epigenetic-based drug combinations but also the molecular mechanisms by which epigenetic modifiers affect multiple myeloma disease progression. This work highlights the need for rational identification of molecular targeted therapy-based drug combinations throughout the progression of multiple myeloma. Beyond multiple myeloma, this platform can be used to identify optimal drug combinations for other cancers as well as provide insight into therapeutically targetable molecular mechanisms that drive cancer progression in various cancer subtypes.

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Protease Inhibitors in Drug Discovery
Protease Inhibitors in Translational Research
Moderator: Steven Wagner, University of California, San Diego
10:40
Ubiquitin Code: Reading, Writing and Editing: Future of Breakthrough Therapies
 
Tauseef Butt
Tauseef Butt
President and CEO
Progenra
About Speaker: Dr. Butt obtained Master’s Degrees in Biochemistry from the University of Dundee, Scotland, UK. His Ph.D. degree in Molecular Biology was awarded by The University of Glasgow, Scotland, He was a Staff Fellow at the National Institutes of Health, Be... Read Full Bio 
 
 
Tauseef Butt
Tauseef Butt
President and CEO
Progenra
 
About Speaker:

Dr. Butt obtained Master’s Degrees in Biochemistry from the University of Dundee, Scotland, UK. His Ph.D. degree in Molecular Biology was awarded by The University of Glasgow, Scotland, He was a Staff Fellow at the National Institutes of Health, Bethesda, MD, before joining SmithKline Beckman (now GSK) Pharmaceuticals. He worked in number of therapeutic areas during his 14 years in the SmithKline organization, where he was Assistant Director in Research and Development. Dr. Butt serves as an Adjunct Professor in Biomedical Engineering at Drexel University, Philadelphia and is active in a number of national and regional professional organizations, including several dedicated to biotechnology. He has a track record of establishing successful biotech companies that are profitable. He has raised several million dollars and brought numerous technologies and products to the market. Dr. Butt is a co-founder of Progenra, Inc.

 
Abstract: The Ubiquitin pathway plays a fundame...Read More 

The Ubiquitin pathway plays a fundamental role in cell physiology. Why nature decorates cellular proteins with eight different poly-ubiquitin structures that extend from seven different lysines on ubiquitin is still largely a mystery, apart from the well-described role of poly-ubiquitin as a signal for proteasome-mediated proteolysis. The physiology that can potentially be influenced by elements of the ubiquitin pathway is vaster than that regulated by simple phosphorylation and dephosphorylation events catalyzed by kinases and phosphatases, owing to the variety of ubiquitin-containing structures that can be produced in cells by ubiquitin conjugating and deconjugating enzymes. Because of this critical role for ubiquitin in physiology and pathology, modulators of ubiquitin pathway targets will be well-represented in future drug pipelines of pharma and biotech. Here, I will describe some prominent ubiquitin ligases and de-ubiquitylases that offer potential as targets for the discovery of breakthrough drugs.

Progenra is currently developing a small molecule that inhibits the cancer-supporting deubiquitylating enzyme USP7. This inhibitor is capable of both killing tumor cells directly and suppressing regulatory T cells, thereby unleashing effector T cells, which identify and kill tumor cells. These results constitute the first example of a small molecule single agent that works by targeting both the tumor itself and the tumor’s ability to escape surveillance and killing by the host immune system and, in addition, by eliminating tumor metastasis. We believe that a small molecule with such a multifaceted anticancer mechanism can replace biologicals as first line cancer therapy.

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11:05
Modulation of Epigenetic Targets for Treatment of Neurodegenerative Disease
 
Tamara Maes
Tamara Maes
CSO
Oryzon
About Speaker: Tamara Maes is BsC in Chemistry and PhD in Biotechnology from the University of Ghent, Belgium and  Co-founder,  CSO and VP of Oryzon Genomics S.A., a clinical stage biopharmarmaceutical company listed on the MADRID Stock Exchange Market (ORY).... Read Full Bio 
 
 
Tamara Maes
Tamara Maes
CSO
Oryzon
 
About Speaker:

Tamara Maes is BsC in Chemistry and PhD in Biotechnology from the University of Ghent, Belgium and  Co-founder,  CSO and VP of Oryzon Genomics S.A., a clinical stage biopharmarmaceutical company listed on the MADRID Stock Exchange Market (ORY).

 
Abstract: Post-translational modifications of h...Read More 

Post-translational modifications of histones are closely associated with changes in transcription. Changes in histone lysine methyl marks are among the most prominent changes, and are mediated by methyltransferases and demethylases. Many diseases are characterized by transcriptional imbalances, and interference with epigenetic targets can be used to modulate these aberrant profiles.

LSD1 inhibition compromises the leukemic stem cell capacity in AML, and drives differentiation of blasts towards a more mature phenotype. Using a tool compound, it was initially shown that MLL translocated cells exhibit special sensitivity to LSD1 inhibition. Treating AML cells with the potent selective LSD1 inhibitor ORY-1001, we confirmed responses at sub-nanomolar to nanomolar concentrations, and revealed that phenotypic changes were accompanied by a shift of the gene expression partially rebalancing the transcriptional profile towards that of normal monocytes/macrophages. We have developed an activity based LSD1 chemoprobe and used it to pull down the protein and to unravel its network of interacting factors in AML. Phase I/IIa data in relapsed or refractory acute leukemia corroborate the in vivo potency of ORY-1001 as an AML differentiating agent. LSD1 inhibitors are also highly active in SCLC subtypes.

The potential role of LSD1 as a drug target is not limited to cancer. LSD1 is expressed in the brain and has a dual role in neuronal stem cell proliferation and neuronal differentiation. Using a chemoprobe based target engagement assay, we have shown that we can modulate LSD1 activity in the brain using the brain penetrant dual inhibitor ORY-2001. Treatment with ORY-2001 rescues memory and behavior alterations in SAMP-8 mice. Phenotypic changes are accompanied by a shift and partial restoration of gene expression patterns in the hippocampus and prefrontal cortex, and also point at ORY-2001 as a modulator of inflammation, corroborated in model for multiple sclerosis. ORY-2001 has finalized Phase I safety and tolerability studies and a Phase II studies are being initiated. 

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11:05
Preclinical Development of a Potent Modulator of the Gamma-Secretase Enzymatic Complex as a Potential Treatment for Alzheimer's Disease
 
Steven Wagner
Steven Wagner
Associate Professor, Neuroscience
University of California San Diego
About Speaker: Dr. Steven Wagner PhD is an Associate Professor in the Department of Neurosciences at UCSD. He has spent over 25 years in the biopharmaceutical industry, and more recently in academia studying translational neuroscience of age-related neurodegenerati... Read Full Bio 
 
 
Steven Wagner
Steven Wagner
Associate Professor, Neuroscience
University of California San Diego
 
About Speaker:

Dr. Steven Wagner PhD is an Associate Professor in the Department of Neurosciences at UCSD. He has spent over 25 years in the biopharmaceutical industry, and more recently in academia studying translational neuroscience of age-related neurodegenerative disorders with an emphasis on Alzheimer’s disease (AD). He led the team that discovered the first non-NSAID-like and truly “Notch-sparing” gamma-secretase modulators and introduced the term “gamma-secretase modulators” (GSMs) in 2005 through the discovery of a novel series of diaryl-2-aminothiazole derivatives that are over 5000-fold more potent at lowering A42 levels than the NSAID-like “substrate-targeted” gamma-secretase modulators, e.g., tarenflurbil. His team also, for the first time, purified to homogeneity the gamma-secretase enzyme complex that is ultimately responsible for generating amyloid β(Aβ) plaques, the diagnostic hallmark of AD. Since moving back to academia, into the Department of Neurosciences at UCSD in June of 2009, his laboratory, in addition to designing/discovering another novel and structurally distinct GSM chemotype, was awarded a Blueprint Neurotherapeutics U01 by NIH/NINDS (one of only seven issued in all of Neurology) to optimize and develop GSMs for the treatment and/or prevention of AD. He is also a member of the NIH Drug Discovery SBIR (ETTN-M)ETTN IRG, Division of Neuroscience, Development and Aging Study Section, a member of the NINDS Special Emphasis Panel for the Blueprint Neurotherapeutics Network, as well as a member of the Cure Alzheimer’s Fund (CAF) Research Consortium and the Scientific Advisory Board for the Alzheimer’s Association’s Collaboration for Cure (C4C).

 
Abstract: Alzheimer’s disease is characte...Read More 

Alzheimer’s disease is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42 amino acid amyloid β peptide, as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance are postulated to initiate and drive the AD pathological process. We initially introduced a novel class of bridged aromatics referred to as gamma-secretase modulators (GSMs) that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides.  These GSMs potently lower Aβ42 levels without inhibiting the gamma-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP.   A number of pharmacological studies and early assessment of toxicology characterizing a highly potent GSM, (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606) as well as a few of its highly potent analogs will be presented.  BPN 15606 displays an impressive in vitro ADMET profile, the ability to significantly lower Aβ42 levels in the CNS of rats and mice at doses as low as 5-10 mg/kg, as well as significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a 3D human neural cell culture model.  Promising results from repeat-dose toxicity studies in rats and dose escalation/repeat dose toxicity studies in non-human primates have designated this GSM as well as a close structural analog for IND-enabling GLP studies and has positioned these GSMs as candidates for human clinical trials.         

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11:30
Targeting the CoREST Complex with Dual Histone Deacetylase and Demethylase Inhibitors
 
Muzhou Wu
Muzhou Wu
Instructor, Dermatology
Boston University School of Medicine
About Speaker: I earned my Ph.D. in Stony Brook University, followed by postdoctoral training at Mount Sinai School of Medicine and Boston University Department of Dermatology. My research focus on the study of epigenetic alternations in melanoma and other malignan... Read Full Bio 
 
 
Muzhou Wu
Muzhou Wu
Instructor, Dermatology
Boston University School of Medicine
 
About Speaker:

I earned my Ph.D. in Stony Brook University, followed by postdoctoral training at Mount Sinai School of Medicine and Boston University Department of Dermatology. My research focus on the study of epigenetic alternations in melanoma and other malignancies. Using novel small molecule inhibitors targeting specific epigenetic protein, we seek to identify transcriptional regulators of cancer progression, and develop targeted epigenetic therapy for melanoma.

 
Abstract: Epigenetic agents have drawn great at...Read More 

Epigenetic agents have drawn great attention as anti-cancer therapies, with several HDAC inhibitors approved for a subset of hematologic malignancies. One of the biggest challenges in targeting epigenetic mechanisms of tumorigenesis is the wide spectrum of effects which restrict the therapeutic window for these compounds. We have developed a series of potent small molecule inhibitors with specificity towards the CoREST epigenetic corepressor complex through a dual-action mechanism targeting LSD1 and HDAC1. These compounds show a unique profile of pharmacologic action with an improved therapeutic window in a variety of cell types. Screening of tumor cell lines for growth inhibitory effects revealed variable efficacy in a broad spectrum of cancers with the most consistent and potent effects seen in human melanomas. The growth of a number of melanoma cell lines was found to be potently inhibited by one of these compounds, Corin; however, primary human melanocytes were relatively resistant to this agent. Transcriptomic analysis revealed that Corin was a more potent inducer of tumor suppressor genes compared to the parent HDAC and LSD1 compounds. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that selectively target particular epigenetic regulatory complexes and offer unique therapeutic opportunities.Beyond the potential value of enhanced specificity and residence time, dual action inhibitors promote a balance in concomitant enzyme blockade at the single cell level and overcome the substantial regulatory challenge of advancing two separate compounds concurrently into clinical trials.

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11:30
Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7
 
Sirano Dhe-Paganon
Sirano Dhe-Paganon
Lead Scientist, Department of Cancer Biology
Dana-Farber Cancer Institute
About Speaker: Structural biologist working on cancer targets. ... Read Full Bio 
 
 
Sirano Dhe-Paganon
Sirano Dhe-Paganon
Lead Scientist, Department of Cancer Biology
Dana-Farber Cancer Institute
 
About Speaker: Structural biologist working on cancer targets.
 
Abstract: Deubiquitinating enzymes (DUBs) have ...Read More 

Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB⋅small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule⋅ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors.

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11:55
Tangled up in Peptides
 
A. James Link
A. James Link
Associate Professor of Chemical and Biological Engineering
Princeton University
About Speaker: Prof. A. James Link earned a BSE from Princeton University and a PhD from Caltech, both in chemical engineering.  He joined the faculty at Princeton in 2007 and is currently an associate professor of chemical and biological engineering and molecular... Read Full Bio 
 
 
A. James Link
A. James Link
Associate Professor of Chemical and Biological Engineering
Princeton University
 
About Speaker:

Prof. A. James Link earned a BSE from Princeton University and a PhD from Caltech, both in chemical engineering.  He joined the faculty at Princeton in 2007 and is currently an associate professor of chemical and biological engineering and molecular biology.  Trained as a protein engineer, Link’s research focus in recent years has been on ribosomally synthesized and post-translationally modified peptides (RiPPs), a diverse and rapidly growing class of natural products. 

 
Abstract: Lasso peptides are a class of natural...Read More 

Lasso peptides are a class of natural products encoded in the genomes of hundreds of different microbes.  These peptides get their name from their slipknotted structure formed via covalent bond formation between the N-terminus of the peptide and a sidechain, generating a macrocyclic “ring.”   The C-terminus of the peptide non-covalently threads through the ring to give the lasso structure.  Because of their entangled structure, lasso peptides are much more protease resistant than their linear counterparts.  This protease resistance is relevant to the biological function of lasso peptides: many of these natural products function as narrow spectrum antimicrobials that are secreted into different environments.  Lasso peptides have been reported as both inhibitors and potentiators of proteases.  In this talk I will introduce the lasso peptide class and discuss my group’s efforts in identifying new lasso peptides from genome sequences.  I will also discuss our efforts in lasso peptide engineering.

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12:20
Lunch Provided by GTCbio
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1:20
Summit Concludes