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Protein Kinases in Drug Discovery

2017-07-232017-11-222017-10-22
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The 2018 agenda is currently being formed.

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BELOW IS THE AGENDA FROM 2017.

2018 Agenda
Day 1 - Wednesday, February 8th, 2017
7:00
Continental Breakfast & Registration
7:45
Welcome & Opening Remarks by Dr. Satish Medicetty, President, GTCbio
10:15
Morning Networking Break
Novel Approaches in Kinase Targeting
Gennady Verkhivker, Schmid College of Science & Technology, Chapman University
10:45
Fractal Nature of Protein Kinase Interior and Design of Allosteric Inhibitors
 
Alexandr Kornev
Alexandr Kornev
Dr., Pharmacology
University of California San Diego
About Speaker: Alexandr Kornev is a project scientist at the University of California San Diego. He studied molecular biophysics in the Moscow Institute of Physics and Technology in Russia, and received his PhD in biophysics at the Semyonov Institute of Chemical Ph... Read Full Bio 
 
 
Alexandr Kornev
Dr., Pharmacology
University of California San Diego
 
About Speaker:

Alexandr Kornev is a project scientist at the University of California San Diego. He studied molecular biophysics in the Moscow Institute of Physics and Technology in Russia, and received his PhD in biophysics at the Semyonov Institute of Chemical Physics. He started his career in the US at UCSD in 2002 studying structural features of protein kinases. His model of protein kinase activation published in 2006 received a worldwide recognition and has become a de facto standard for active protein kinase structures. His scientific interests include computational studies of allosteric regulation of protein kinases and proteins in general.

 
Abstract: Fractal like objects are ubiquitous in nature. Their origin is often related to random self-organizing processes. Proteins, being a product of rand...Read More 

Fractal like objects are ubiquitous in nature. Their origin is often related to random self-organizing processes. Proteins, being a product of random folding of polypeptide chains, also demonstrate fractal like properties. Recent studies of protein kinase dynamics indicate that their fractal properties can be intimately involved in their function. It has been demonstrated that protein fractal structures are volatile and can change dramatically upon small molecule binding. This opens the door to an explanation of long distance allosteric signaling that is based solely on protein dynamics and does not involve any structural changes. Our work on protein kinases show that densely packed regions (communities) in fully functional kinases correspond to the well known functional elements of the kinase core. Furthermore, residues with high centrality that serve as major communicators between the communities are very well known to be critical for protein kinase function. These findings support the idea that fractal nature of protein kinases is a conserved feature in the whole protein kinase family. This makes studies of protein fractal structure an important analytical tool that can shed light on the most critical regulatory mechanisms in molecular biology and to create foundation for design of allosteric inhibitors.

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11:10
Targeting AGC Kinases with Selective and Highly Soluble Inhibitors
 
Oliver Plettenburg
Oliver Plettenburg
Professor, Institute of Medicinal Chemistry
Helmholtz Zentrum München, German Research Center for Environmental Health
About Speaker: Oliver Plettenburg is Director of the Institute of Medicinal Chemistry at the Helmholtz Center for Environmental Health in Munich and Professor for Medicinal Chemistry at Leibniz Universität Hannover. Previously he held various positions within the ... Read Full Bio 
 
 
Oliver Plettenburg
Professor, Institute of Medicinal Chemistry
Helmholtz Zentrum München, German Research Center for Environmental Health
 
About Speaker:

Oliver Plettenburg is Director of the Institute of Medicinal Chemistry at the Helmholtz Center for Environmental Health in Munich and Professor for Medicinal Chemistry at Leibniz Universität Hannover. Previously he held various positions within the pharmaceutical industry, last as Head of Biosensors & Chemical Probes in Sanofi’s Diabetes Division. The group’s main responsibility was to support evaluation of validity of novel targets, provide tools to visualize pathologically relevant processes, to develop new methods to quantify important biomarkers and to explore new treatment options at the drug-device interface.

Oliver was with Sanofi for 14 years. Before joining the Diabetes Division he worked as a project leader in several medicinal chemistry projects in the area of Diabetes and Cardiovascular Diseases and was deeply involved in the Chemical Biology approach within Aventis.

After receiving his PhD in organic chemistry, he joined The Scripps Research Institute as a postdoctoral fellow, working in the group of Chi-Huey Wong on the total synthesis of glycosyl sphingosides.

 
Abstract: Kinase inhibitors frequently suffer from unfavorable solubility and selectivity issues. In this presentation the development of inhibitors of rho k...Read More 

Kinase inhibitors frequently suffer from unfavorable solubility and selectivity issues. In this presentation the development of inhibitors of rho kinase, an AGC kinase acting as a key modulator of smooth muscle contractility and involved in several vascular diseases like hypertension or diabetic nephropathy, is discussed. Optimization of the lead compound resulted in the discovery of a new series of compounds with excellent selectivity and very good solubility. The binding mode will discussed and the underlying principle will be applied to another member of the AGC kinase family, PKC beta. The results of the lead optimization of that series will also be presented, leading again to soluble and specific inhibitors with good oral bioavailability.

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11:35
Structure-Kinetic Relationship Study of CDK8/CycC Specific Compounds and Beyond
 
Elisabeth Schneider
Elisabeth Schneider
Robert-Huber fellow, Emeritusgruppe Huber
Max-Planck-Institute of Biochemistry
About Speaker: Elisabeth V. Schneider, Ph.D., received her Ph.D. at Technische Universität München under supervision of Prof. Dr. Dr. h. c. Robert Huber, Max-Planck-Institute of Biochemistry, working at the laboratories of Proteros Biostructures GmbH. Currently, ... Read Full Bio 
 
 
Elisabeth Schneider
Robert-Huber fellow, Emeritusgruppe Huber
Max-Planck-Institute of Biochemistry
 
About Speaker:

Elisabeth V. Schneider, Ph.D., received her Ph.D. at Technische Universität München under supervision of Prof. Dr. Dr. h. c. Robert Huber, Max-Planck-Institute of Biochemistry, working at the laboratories of Proteros Biostructures GmbH. Currently, she holds the Robert-Huber fellowship. Dr. Schneider is a specialist on kinases, especially Cyclin-dependent kinases. She solved the first crystal structure of the human CDK8/CycC complex and collaborated on several projects with partners from industry and academia in order to identify CDK8/CycC specific compounds. In addition, her current work involves further protein complexes interacting with CDK8 such as the CKM module of the Mediator of transcription and members of the JAK family, including protein purification, biochemical assays, compound screening and kinetic profiling as well as crystallographic studies.

 
Abstract: In contrast to the very well explored concept of structure–activity relationship, similar studies are missing for the dependency between bind...Read More 

In contrast to the very well explored concept of structure–activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure–kinetic relationship (SKR). Here the authors present a SKR study on the example of the cyclin-dependent kinase 8 (CDK8) / cyclin C (CycC) complex, a potent oncogene of clinical relevance. Based on a high throughput binding assay, fragments for a subsequent so-called back to front approach were identified: the scaffold moiety of these compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. Moreover, the kinetic profiling of these compounds is completed with thermodynamic data. (Schneider EV, Böttcher J, Huber R, Maskos K, Neumann L. Proc Natl Acad Sci U S A. 2013;110(20):8081-6.)

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12:00
Lunch Provided by GTCbio
1:15
Discovery of a Covalent ERK1/2 Inhibitor
 
Lixin Qiao
Lixin Qiao
Sr. Principal Scientist, Medicinal Chemistry
Celgene
About Speaker: Lixin Qiao received his Ph.D. in Organic Chemistry at Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences, and completed his postdoctoral fellowship at Georgetown University Medical School. After working at ArQule for 5 years ... Read Full Bio 
 
 
Lixin Qiao
Sr. Principal Scientist, Medicinal Chemistry
Celgene
 
About Speaker:

Lixin Qiao received his Ph.D. in Organic Chemistry at Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences, and completed his postdoctoral fellowship at Georgetown University Medical School. After working at ArQule for 5 years in compound library design and high-throughput synthesis, he joined Avila Therapeutics Inc. in 2008, which later became Celgene Avilomic Research. His work has been focused on the structure-based drug discovery of irreversible inhibitors on protein kinases and proteases. He was the project leader of ERK program, carrying the ERK inhibitor from the discovery to early development.

 
Abstract: MAPK (RAF/MEK/ERK) kinase pathway is a validated pathway for cancer therapeutic intervention (e.g. melanoma). Blockade of this pathway is expected ...Read More 

MAPK (RAF/MEK/ERK) kinase pathway is a validated pathway for cancer therapeutic intervention (e.g. melanoma). Blockade of this pathway is expected to shut down an mTORCi escape mechanism involving activation of MEK pathway signaling. Though some BRAF and MEK inhibitors have been FDA-approved or are at late stage of clinical trials, the resistance to BRAFi and MEKi presents an emerging unmet medical need. ERK is a major signaling convergence point in human cancers. Tumor biology data suggests that targeting ERK hold high potential to overcome or prevent resistance from BRAFi and MEKi. Using structure-based drug design, we discovered CNX-5269, which forms covalent bond with the Cys in the ATP binding sites of ERK1/2. The enhanced pharmacodynamimcs effect was demonstrated by prolonged inhibition of p-RSK and extended ERK occupancy recovery after compound washout. CNX-5269 inhibited the cell growth against not only a broad spectrum of BRAF- and KRAS-mutant cell lines, but also against vemurafinib- and trametinib-resistant A375R clones and trametinib-resistant HCT116R polyclonal cells. In vivo, tumor growth inhibition results in BRAFV600E (A375, LOX IMVI melanoma) and KRasG13D (HCT116 colon) xenograft models correlated with ERK occupancy in tumor tissues, as presented in QD and QOD dose regimen.

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1:40
A Water-Mediated Allosteric Network Governs Activation of the Mitotic Kinase Aurora A
 
Nicholas Levinson
Nicholas Levinson
Assistant Professor, 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
Assistant Professor, 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: The protein kinase Aurora A plays essential roles in centrosome maturation and mitotic spindle assembly. The spindle assembly functions of Aurora A...Read More 

The protein kinase Aurora A plays essential roles in centrosome maturation and mitotic spindle assembly. The spindle assembly functions of Aurora A are dependent on the spindle protein Tpx2, which both recruits the kinase to the spindle and allosterically activates it. Unlike related kinases, activation of Aurora A by Tpx2 does not require phosphorylation on the activation loop, and involves a robust 50-fold increase in activity. Surprisingly, x-ray structures do not reveal any changes in the kinase active site upon Tpx2 binding, and the activation mechanism remains mysterious. We used a site-specific vibrational probe to track the conformation of the DFG motif of Aurora A in solution, and detected a conformational equilibrium between inactive DFG-Out and active DFG-In states that is shifted towards the DFG-In state by Tpx2. Using intramolecular FRET, we show that the activation loop also undergoes a nanometer-scale conformational change in response to Tpx2 binding that is tightly coupled to the DFG equilibrium. In addition, Tpx2 further activates the kinase by stabilizing a unique water-mediated allosteric network that functions as a polar analog of the regulatory spine by tightly coupling the kinase C-helix to the active site. Alternative forms of the water network are found in many related kinases, and when transplanted into Aurora A can support activation of the kinase by Tpx2, but not by phosphorylation. This suggests that variations in the water networks across kinase subfamilies serve to diversify regulatory responses by tuning the extent of allosteric coupling between structural elements of the kinase domain.

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2:05
Phosphatase and Kinase Activity Profiling in Clinical Tissues
 
Rob Ruijtenbeek
Rob Ruijtenbeek
Vice President Research & Development
PamGene
About Speaker: Dr Rob Ruijtenbeek is Vice President R&D at Pamgene (‘s-Hertogenbosch, The Netherlands), where he heads a multidisciplinary R&D team performing research and development of peptide microarray products and applications in the field of kinases... Read Full Bio 
 
 
Rob Ruijtenbeek
Vice President Research & Development
PamGene
 
About Speaker:

Dr Rob Ruijtenbeek is Vice President R&D at Pamgene (‘s-Hertogenbosch, The Netherlands), where he heads a multidisciplinary R&D team performing research and development of peptide microarray products and applications in the field of kinases, phosphatases, nuclear receptors and other drug targets. The focus of his current research is the application of peptide microarrays in biomarker discovery in clinical oncology, predicting response to therapy. He is affiliated with the medicinal chemistry and chemical biology group of Utrecht University, where new applications for the peptide microarray technology are investigated in the area of pharmaceutical research & development. This has resulted in multiple scientific publications, patent applications and commercialized products.

Rob Ruijtenbeek holds a M.Sc. degree in both biochemistry and organic chemistry from the University of Nijmegen (1996) and received his Ph.D. degree in 2001 at the faculty of Pharmacy of the University of Utrecht, The Netherlands.

 
Abstract: Protein tyrosine phosphatases (PTPs) and protein tyrosine and serine/threonine kinases (PTKs, STKs) are important regulators of signal transduction...Read More 

Protein tyrosine phosphatases (PTPs) and protein tyrosine and serine/threonine kinases (PTKs, STKs) are important regulators of signal transduction pathways in tumour and immune cells, and key targets in precision medicine. Currently, most analytical methods focus on the detection of these crucial enzymes at RNA or protein abundance levels. We developed an innovative method to monitor multiple phosphatase and kinase activities in patient-derived materials like blood and tumour tissues. The target pathways, all controlled by both phosphatases and kinases, include the checkpoint and immune receptors like PD1, CTLA4, LAG3, 4-1BB, CD40, CD20, OX40, TIGIT and GITR. This substrate-specific assay is a valuable, novel tool for biomarker discovery in (immuno-)oncology.

Here we will present a multiplex PTP peptide microarray test and its application in biomarker discovery for tailoring targeted therapies (triple-T approach). It is combined with kinase activity profiling on the same platform. We investigated renal tumour tissues with high and low levels of TILs (tumour-infiltrating lymphocytes) as well as peripheral blood mononuclear cells from melanoma patients treated with checkpoint blockers.

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2:30
Dynamics of Beta 4 Loop Control BRAF Dimerization and Paradoxical Activation
 
Daniel Whalen
Daniel Whalen
Postdoctoral Research Fellow
Genentech
About Speaker: Dan Whalen is a Postdoctoral research fellow in the Department of Protein Chemistry and Structural Biology at Genentech, in Sarah Hymowitz’ s lab. He is focused on the study of protein kinases, using biochemical, biophysical and structural techniqu... Read Full Bio 
 
 
Daniel Whalen
Postdoctoral Research Fellow
Genentech
 
About Speaker:

Dan Whalen is a Postdoctoral research fellow in the Department of Protein Chemistry and Structural Biology at Genentech, in Sarah Hymowitz’ s lab. He is focused on the study of protein kinases, using biochemical, biophysical and structural techniques, with a particular interest in the RAF/MEK/ERK MAPK pathway.

In work recently published in Cancer Cell alongside colleagues Shiva Malek and Scott Foster et al., he solved several crystal structures of a short in-frame deletion BRAF mutant. These mutants, analogous to the recurrent EGFR exon 19 deletion, are activating in patient tumor samples.

The crystal structures revealed the activation mechanism of this emergent class ofactivating mutations for the first time; that the deletion biases the conformation of αC to the ‘ in’ position. Restraining αC conformation in this manner confers resistance to αC “out” inhibitors vemurafenib and lapatinib.

He previously studied for his DPhil at the University of Oxford, in the lab of Christian Siebold, where he solved several novel protein crystal structures, including the Smoothened ectodomain and multiple Sonic Hedgheog-glycosaminoglycan complex crystal structures. These data were leveraged to provide new insights into the regulation of Smoothened and the Hedgehog morphogenetic pathway.

 
Abstract: The Ras/RAF/MEK/ERK signaling pathway (MAPK pathway) plays a major role in growth factor-mediated cell proliferation and is frequently activated in...Read More 

The Ras/RAF/MEK/ERK signaling pathway (MAPK pathway) plays a major role in growth factor-mediated cell proliferation and is frequently activated in human cancer.

Although clinical success of RAF inhibitors have been demonstrated in RAF mutant cancers, in Ras-driven malignancies with WT RAF, these inhibitors have been shown to drive tumourgenesis. A chemically diverse range of ATP competitive inhibitors exhibit this antithetical effect, termed Paradoxical Activation.

RAF kinase dimerization is a key regulatory event of the pathway, and inhibitor binding is thought to activate RAF by inducing dimerization, membrane localization and interaction with Ras-GTP. Intriguingly, the degree to which different inhibitors alter the RAF dissociation constant (KD) differ by orders of magnitude, yet X-ray studies show little structural change between different inhibitor complexes. Further, the degree to which inhibitors drive dimerization does not correlate with paradoxical activation.

Using biophysical measurements of RAF kinase inhibitor complexes, we are beginning to unravel the kinetics of inhibitor binding, their distinct effects upon RAF dimerization and paradoxical activation.

We have performed detailed structural analysis of RAF kinase inhibitor complexes, identifying a beta turn in the beta4 loop which participates in the RAF dimerization interface, which communicates with the ATP/drug binding pocket and communities of residues important for the RAF catalytic cycle.

We present the structure of BRAF L514F, a mutation in the beta turn which drives dimerization. Structural analysis reveals that the mutant phenylalanine packs into a previously unidentified allosteric pocket, stabilizing the loop and priming the mutant protein for dimerization.

This work provides new insights into the therapeutic use of ATP-competitive inhibitors and provides a framework for aiding future drug design efforts to evade paradoxical activation.

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2:55
Afternoon Networking Break
Kinome Selectivity and Translation to Clinical Safety
Daniel Whalen, Genentech
3:25
Kinase Screening and Profiling One Platform Fits Them All
 
Said Goueli
Said Goueli
Senior Research Fellow, Research and Development
Promega
About Speaker: Said Goueli is a Senior Research Fellow at Promega Corporation. He is the founder of the cell signaling group, where his focus is mainly directed at biochemical assays to study cell signaling and, most recently, on cell based technologies to monitor ... Read Full Bio 
 
 
Said Goueli
Senior Research Fellow, Research and Development
Promega
 
About Speaker:

Said Goueli is a Senior Research Fellow at Promega Corporation. He is the founder of the cell signaling group, where his focus is mainly directed at biochemical assays to study cell signaling and, most recently, on cell based technologies to monitor cellular metabolites in normal and abnormal cell growth. In addition to his role at Promega, Said holds a joint appointment as clinical Professor in the department of Pathology and Lab Medicine at the University of Wisconsin – Madison.

Said has pioneered novel technologies that advanced research in cell signaling. He was one of the first to develop anti phosphospecific antibodies, and has over 80 peer reviewed publications and holds over 15 issued and several pending patents on kinase assays (radioactive, fluorescent, and luminescent) and related technologies. He has also developed novel technologies in monitoring the activity of protein phosphatases and is currently developing luminescent assays for monitoring the activity of phospholipid phosphatases.

Said has also developed a novel strategy to monitor the modulation of Gs and Gi-Protein Coupled Receptors (GPCR), GTPases, and Phosphodiesterases. His interest has expanded most recently to newer areas of cell signaling research as evidenced by his development of universal assays for all classes of methyltransferases.

 
Abstract: Broad utility of one assay for screeining and profiling kinases Homogenous and HTS formatted assay platform Low False hits ...Read More 
  • Broad utility of one assay for screeining and profiling kinases
  • Homogenous and HTS formatted assay platform
  • Low False hits and ease of lead optimzation of identified hits
  • Minitiurization to high density plate formats
  • Cost effective and simple assay to perform
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3:50
Docking and Scoring versus Ligand-based Methods in Identifying Kinase Inhibitors
 
Istvan Enyedy
Istvan Enyedy
Senior Scientist, Chemistry
Biogen
About Speaker: In the past 18 years Istvan J Enyedy has been involved in new target evaluation, hit finding, and hit-to-lead optimization projects for several types of target classes using both ligand and structure-based methods. He is coauthor on more than 40 publ... Read Full Bio 
 
 
Istvan Enyedy
Senior Scientist, Chemistry
Biogen
 
About Speaker:

In the past 18 years Istvan J Enyedy has been involved in new target evaluation, hit finding, and hit-to-lead optimization projects for several types of target classes using both ligand and structure-based methods. He is coauthor on more than 40 publications and 13 patents/applications. He received his PhD in 1998 at Catholic University of America, Washington DC, and did postdoctoral training in Dr. Shaomeng Wang’s group at Georgetown University Medical Center, Washington DC. Between 2001 and 2008 he worked at Bayer Pharmaceuticals, West Haven CT and Novartis Institutes for Biomedical Research in Cambridge MA. Since August 2008 he has been working at Biogen Idec, in Cambridge MA.

 
Abstract: We have developed a protocol for generating a negative image, fake ligand, of the binding site of a target protein form the output of computational...Read More 

We have developed a protocol for generating a negative image, fake ligand, of the binding site of a target protein form the output of computational solvent mapping. We used fake ligands to generate queries for ROCS, a ligand-based method, and to define the search space of the docking programs FRED and HYBRID. Fake ligands performed comparably to or better than ligands from crystal structures for a set of nine kinases. We have also tested Kriging, a new ligand-based method that shows promise in predicting activity when enough experimental data is available.

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4:15
Approaches to Kinase Selectivity - the Obvious and Nonobvious...
 
Huifen Chen
Huifen Chen
Senior Scientist
Genentech
About Speaker: ... Read Full Bio 
 
 
Huifen Chen
Senior Scientist
Genentech
 
About Speaker:
 
Abstract: Protein kinases constitute one of the largest protein families with over 500 members, and are involved in many critical cellular processes and sign...Read More 

Protein kinases constitute one of the largest protein families with over 500 members, and are involved in many critical cellular processes and signaling pathways. Due to the important roles kinases play in biological processes they have been heavily pursued as therapeutic targets, especially in oncology and inflammation. One of the major concerns for kinase targets is selectivity over other kinases since most small molecule kinase inhibitors bind to the highly conserved ATP binding site. The most common approach to achieve selectivity is to identify sequence differences in the binding site and incorporate designs to insult the off-targets while maintaining potency against the target. In this presentation I will show you several examples where we have exploited both the obvious (sequence-based) and nonobvious features (structural plasticity and pharmacophore manipulation) to achieve either broad kinase selectivity or selectivity over closely related kinases.

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4:40
The Discovery of Rociletinib, a Mutant-Selective Covalent Inhibitor of EGFR
 
Deqiang Niu
Deqiang Niu
Director, Chemistry
Celgene
About Speaker: Deqiang Niu, Ph.D., is director of medicinal chemistry at Celgene Avilomics Research in Cambridge, Massachusetts. He oversees the medicinal chemistry research and the HTMC lab (High Throughput Medicinal Chemistry). Dr. Niu has been with Celgene Avilo... Read Full Bio 
 
 
Deqiang Niu
Director, Chemistry
Celgene
 
About Speaker:

Deqiang Niu, Ph.D., is director of medicinal chemistry at Celgene Avilomics Research in Cambridge, Massachusetts. He oversees the medicinal chemistry research and the HTMC lab (High Throughput Medicinal Chemistry). Dr. Niu has been with Celgene Avilomics Research since early 2008 - he joined Avila Therapeutics in 2008, and became part of Celgene Corp. through an acquisition in 2012. Before his current position, Dr. Niu had worked at Enanta pharmaceuticals and Biogen Idec, both located in the greater Boston area, with increased responsibilities. Dr. Niu's drug discovery experience covers infectious, oncology and autoimmune diseases. The molecular targets of interest include proteases, kinases, protein synthesis and targeted covalent inhibitors for many protein targets. He had been involved in projects that yielded multiple preclinical, clinical candidates and an approved drug.

Dr. Niu holds B.S. and M.S. degrees from Peking University and a Ph.D. in organic chemistry from New York University. Dr. Niu completed his postdoctoral training with Professor Gilbert Stork at Columbia University, where he completed the total synthesis of Quinine.

 
Abstract: Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to EGFR tyrosi...Read More 

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Unfortunately, most patients develop resistance due to a secondary mutation at T790M (the gatekeeper mutation) within exon 20 of EGFR. This mutation accounts for approx. 60% of all resistance cases. Although second generation irreversible TKIs (e.g. Afatinib, dacomitinib, neratinib) are more potent against the T790M mutation, their high potency against wild type EGFR results in dose-limiting toxicities. Through structure based drug design and extensive structure activity relationship (SAR) efforts, we identified a series of irreversible compounds that selectively and potently inhibit both EGFR T790M and the initial activating EGFR mutations (e.g. DelE746-A750), and importantly, are selective against wild type EGFR. These compounds have the potential to treat NSCLC patients with EGFR mutations without causing wild type EGFR related toxicities. The design strategy and SAR leading to the discovery of rociletinib will be discussed.

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5:15
Networking Reception & Poster Session
Day - 2 Thursday, February 9th, 2017
7:30
Continental Breakfast
Tools and Technologies in Kinase Drug Discovery
Shuxing Zhang, MD Anderson Cancer Center
8:00
Strategies and Outcomes for Fragments for Kinases
 
Rod Hubbard
Rod Hubbard
Professor
Vernalis and University of York
About Speaker: Rod Hubbard has been working with methods for analysis and exploitation of protein structure for nearly 35 years. In the 1980s, he developed molecular graphics and modelling methods. In the 1990s he helped build the Structural Biology Lab at the Univ... Read Full Bio 
 
 
Rod Hubbard
Professor
Vernalis and University of York
 
About Speaker:

Rod Hubbard has been working with methods for analysis and exploitation of protein structure for nearly 35 years. In the 1980s, he developed molecular graphics and modelling methods. In the 1990s he helped build the Structural Biology Lab at the University of York and determined the structure of many proteins of therapeutic importance; this was combined with studies of protein-ligand interactions and some of the first work in finding small fragments that bind to protein targets. In 1997, he was a founding SAB member of the structure-based pharmaceutical company that became Vernalis. Since 2001, he has spent varying amounts of his time at Vernalis, establishing and applying structure and fragment-based methods for drug discovery. He currently splits his time between York and Vernalis; in addition, he is a member of various boards and panels for the UK Research Councils and consults with pharmaceutical and technology companies around the world.

 
Abstract: Many companies (including Vernalis) have conducted a number of fragment based discovery projects against different kinases over the past 15 years. ...Read More 

Many companies (including Vernalis) have conducted a number of fragment based discovery projects against different kinases over the past 15 years. In this talk, I will draw mainly on the Vernalis experience to review the approach and then use a number of examples (including DYRK1, PAK1, Pim1, Chk1 and LRRK2) to illustrate the following features:

  • Fragments and selectivity
  • Using crystallographic surrogates for challenging kinases
  • Rapid generation of tool compounds to test kinase biology
  • Integrating fragments with HTS
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8:25
Allosteric Regulatory Mechanisms of Hsp90 Chaperone Interactions with Protein Kinase Clients: Design of Synergistic Hsp90 and Kinase Inhibitors using Multiscale Modeling, Computational Systems Biology and Biophysical Studies
 
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
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 Hsp90-Cdc37 chaperone machinery and protein kinases in biology and disease have stimulated extensive structural and functi...Read More 

The synergistic roles of 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. The overarching goal of dissecting molecular principles underlying chaperone-based modulation of kinase activity and differentiation of protein kinase clients and is fundamental to understanding activity of many tumor-inducing signaling proteins. By integrating microsecond multiscale simulations of Hsp90 chaperone and tyrosine kinases clients with FRET experiments with computational systems biology of chaperone-kinase networks, we characterize an allosteric cross-talk between the Hsp90-Cdc37 chaperone and protein tyrosine kinases at the atomic level. We have systematically characterized conformational landscapes of protein tyrosine kinases clients, demonstrating that client status may be strongly linked with high conformational mobility of their inactive states. Integration of computational and experimental approaches was leveraged to probe structural mechanisms of the Hsp90-Cdc37 chaperone binding with the Cdk4 kinases. Protein kinase clients of Hsp90 chaperone display the increased nucleotide diversity and harbor more oncogenic mutations than nonclient kinases. We have also analyzed how ATP-competitive kinase inhibitors and allosteric modulators targeting Hsp90 chaperone may act synergistically and exert their pharmacological effect by antagonizing the Hsp90-kinase interactions and depriving the client kinase of access to the molecular chaperone. Our study offers a systems-based perspective on drug design by unravelling complex relationships between signaling pathways, cellular protein kinase networks and binding specificity of targeted kinase drugs. We discuss how these approaches can exploit advances in chemical biology and network science to develop novel strategies for rationally tailored and robust personalized drug therapies.

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8:50
Thinking Ahead of Time: Application of Next Generation Modeling to 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 Chemistryat theNovartis Institutes for BioMedical Research (NIBR). José joined Novartis in 2010. Previously hehadbeen with the Schering-Plough Research Institute... Read Full Bio 
 
 
Jose Duca
Head, Computer-Aided Drug Discovery
Novartis
 
About Speaker:

José is Global Head of Computer Aided Drug Discovery (CADD), part of Global Discovery Chemistryat theNovartis Institutes for BioMedical Research (NIBR).

José joined Novartis in 2010. Previously hehadbeen with the Schering-Plough Research Instituteand Merck Research Laboratoriesin Kenilworth, NJ, USAfor 10 years where hehad increasing responsibilities in the CADD group.His scientific fields of expertise within computational chemistry comprisemolecular thinking, modeling,ab initiocalculations, molecular recognition, QM-MM methods, solvationand 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 theCollege of Pharmacy at the University of Illinois at Chicago as a Postdoctoral Fellow.

 
Abstract: 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...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 from the field of kinases.

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9:15
Mutation of a Conserved Allosteric Node Impacts All Dynamic Facets of Protein Kinase Activity
 
Lalima Ahuja
Lalima Ahuja
Department of Pharmacology and Chemistry and Biochemistry
University of California San Diego
About Speaker: ... Read Full Bio 
 
 
Lalima Ahuja
Department of Pharmacology and Chemistry and Biochemistry
University of California San Diego
 
About Speaker:
 
Abstract: The expertise of Protein Kinases lies in their dynamic structure where-in they are able to modulate cellular signaling by their phosphotransfer act...Read More 

The expertise of Protein Kinases lies in their dynamic structure where-in they are able to modulate cellular signaling by their phosphotransfer activity. With only a few hundreds of Protein Kinases regulating the billion genes in a human cell; Protein Kinases play a pivotal role in health and disease. Many Protein Kinase mutation are known to cause pathophysiologies and their drug-manipulation is one of the key strategies of biomedical research. The impact of these mutations are not very well understood and rigid-body models of protein structure do not allow for efficient drug discovery. The present study dwells upon understanding the working of the Protein Kinase-molecular switch as an Allosteric network of “Communities” comprised of the residues that form the conserved Protein Kinase domain. Girvan-Newman algorithm based Community Maps on the Dynamically Simulated structures of Protein Kinase A allow for a molecular explanation of Protein allosteric behavior coupled to its Catalytic Cycle. A conserved allosteric node at Tyr 204 is used as a model to provide for direct understanding of these Community Maps using conventional biochemical experiments. These studies pave the way for the yet unexplored aspect of Protein Kinase manipulation that holds promise in understanding their mutations and plausible designing of allosteric inhibitors.

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9:40
Morning Networking Break
Tools and Technologies in Kinase Drug Discovery (Cont’d)
Shuxing Zhang, MD Anderson Cancer Center
10:10
Profiling Kinase Inhibitors with Diverse Inhibition Modes: Allosteric, Protein-Protein Interactions, Covalent, Pseudo Kinase Domain and Extended Target Residence Time
 
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
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: In the beginnings of kinase drug discovery mainly ATP competitive inhibitors were developed. However in the last years the diversity of inhibitors ...Read More 

In the beginnings of kinase drug discovery mainly ATP competitive inhibitors were developed. However in the last years the diversity of inhibitors were extensively expanded and a plethora of novel inhibition strategies was pursued such as: Allosteric inhibition, targeting protein-protein interactions, covalent inhibitors, compounds addressing the pseudo kinase domains and inhibitors with extended target residence time. These multiple strategies require rapid tool and technology innovations to be able to identify these various types of inhibitors and to quantify their efficacy. By combining a set of innovative technologies such as kinetic high throughput binding assays, nanoDSF, high sensitivity ITC, enzyme assays and single molecule gene expression profiling Proteros Biostructures has established a technology platform that is ideally suited to support drug discovery for all these novel inhibitor types. The presentation will provide example data for all the different inhibition strategies and exemplify how they can be implements in drug discovery programs.

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10:35
Chemistry of Degradation Pathways
 
Alexander Statsyuk
Alexander Statsyuk
Assistant Professor, Pharmacological and Pharmaceutical Sciences
University of Houston
About Speaker: Alexander Statsyuk obtained his PhD degree at the University of Chicago in 2006 working with Sergey A Kozmin, where he synthesized natural product Bistramide A and showed that bistramide A inhibits actin polymerization. He then completed his postdoct... Read Full Bio 
 
 
Alexander Statsyuk
Assistant Professor, Pharmacological and Pharmaceutical Sciences
University of Houston
 
About Speaker:

Alexander Statsyuk obtained his PhD degree at the University of Chicago in 2006 working with Sergey A Kozmin, where he synthesized natural product Bistramide A and showed that bistramide A inhibits actin polymerization. He then completed his postdoctoral work with Kevan M Shokat at UCSF, where he was working on the development of chemical cross-linkers to identify upstream kinases of protein phosphorylation sites. In 2010, he started his independent career at the Department of Chemistry Northwestern University and then moved to the University of Houston in 2016. His research program addresses the need of developing chemical probes to study the ubiquitin system. Alexander Statsyuk is a recipient of Pew Scholarship award and is an author of 20 manuscripts and has 9 pending patent applications.

 
Abstract: E3 ligases are considered risky drug targets and difficult to pursue. The reason for this is two-fold. First, E3 ligase enzyme mechanisms are still...Read More 

E3 ligases are considered risky drug targets and difficult to pursue. The reason for this is two-fold. First, E3 ligase enzyme mechanisms are still being uncovered preventing the design of the mechanism-based inhibitors. Second, in contrast to protein kinases and methyl transferases, the assays to screen for inhibitors of E3s are complicated and require E1, E2, E3 enzymes, Ub, ATP and additional reagents to quantify a mixture of the reaction products. In this lecture, we will outline thoughts on general approaches to design E3 ligase inhibitors. We will also outline our progress toward discovery and the design of selective inhibitors of E3 ligases using novel E3 ligase probe UbFluor that we have developed.

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11:00
Personalized Cancer Therapy Based on Kinase Inhibitor Polypharmacology
 
Shuxing Zhang
Shuxing Zhang
Associate Professor, Experimental Therapeutics
MD Anderson Cancer Center
About Speaker: Prof. Shuxing Zhang has been working in the area of drug discovery and computational modeling for nearly 20 years in academia, industry, and government agencies. Currently he is Associate Professor at The University of Texas MD Anderson Cancer Center... Read Full Bio 
 
 
Shuxing Zhang
Associate Professor, Experimental Therapeutics
MD Anderson Cancer Center
 
About Speaker:

Prof. Shuxing Zhang has been working in the area of drug discovery and computational modeling for nearly 20 years in academia, industry, and government agencies. Currently he is Associate Professor at The University of Texas MD Anderson Cancer Center and Director of Molecular Modeling and Structural Biology Core established based on his unique cheminformatics, bioinformatics, and systems chemical biology integrated platform. Using these state-of-the-art technologies, Dr. Zhang has developed a variety of promising therapeutic agents currently undergoing preclinical or clinical studies. In 2009, he co-founded PHusis Therapeutics to translate his Akt-targeted kinase inhibitors currently in IND application and recently he started another company TheraXen Technology to commercialize his PH domain-based technologies. These intensive experiences signify Dr. Zhang’s resolve as a scientific entrepreneur to translate his laboratory discoveries to product commercialization and clinical patient treatment. Dr. Zhang has received numerous prestigious awards and his pioneering studies are widely supported by NIH, DOD, NSF, and many other funding agencies.

 
Abstract: The conventional paradigm of single drug, single target has been shifted towards one drug, multiple targets. Therefore, in recent years drug polyph...Read More 

The conventional paradigm of single drug, single target has been shifted towards one drug, multiple targets. Therefore, in recent years drug polypharmacology has gained significant attentions. However it is impossible to exhaustively cover the chemical-biological space with wetlab experiments. To address this issue, we attempt to model drug polypharmacology and thus implemented an integrative, multi-modal computational framework. It is based on chemical-genomic similarity, structure-based approaches, and graph theory combined with big data analysis. We employed this platform to repurpose FDA-approved drugs to treat one of our patients with aberration of ACK1 kinase, a novel cancer target in multiple cancers but no inhibitor available. We demonstrated that ACK1 is significantly inhibited by four of our 10 in silico hits. In particular, the inhibition by Dasatinib is as strong as IC50=1nM. We expect that this framework can be easily extended to a broad range of drug polypharmacology and repositioning studies, especially for personalized cancer therapies.

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Round Table Discussions
12:25
Lunch Provided by GTCbio
Joint Session: Translational Assay Development
Roland Wolkowicz, San Diego State University
1:35
Go With the Flow: Development of in Vitro Potency Tests for Stem Cell Therapies
 
Sofie PattjIn
Sofie PattjIn
CTO
ImmunXperts SA
About Speaker: Sofie Pattijn (CTO and founder, ImmunXperts) has over 20 years of experience in the field of immunogenicity assessment (vacci nes and biotherapeutics) and in vitro assay development. She has extensive hands-on lab experience and has managed and coach... Read Full Bio 
 
 
Sofie PattjIn
CTO
ImmunXperts SA
 
About Speaker:

Sofie Pattijn (CTO and founder, ImmunXperts) has over 20 years of experience in the field of immunogenicity assessment (vacci nes and biotherapeutics) and in vitro assay development. She has extensive hands-on lab experience and has managed and coached several In Vitro teams over the last decade. From 2008 till 2013 she was Head of the In Vitro Immunogenicity group at AlgoNom ics (Ghent, Belgium) and Lonza Applied Protein Services (Cambridge, UK). Prior to that, she worked at Innogenetics, Belgium for over 15 years.

 
Abstract: Cellular therapies are becoming more and more important for the treatment of cancer, autoimmune disorders, hematologic malignancies and tissue dama...Read More 

Cellular therapies are becoming more and more important for the treatment of cancer, autoimmune disorders, hematologic malignancies and tissue damage. As this field develops, the ability to produce large quantities of biological products with predictable quality and quantifiable potency is of great importance. Potency testing is the quantitative measure of a biological activity which is linked to relevant biological properties of a product. The biological activity measured should be closely related to the product’s intended biological effect and ideally it should be related to the product’s clinical response. Technologies such as flow cytometry contribute to the development and application of complex in vitro assays representing the in vivo biological activity of the cellular therapy. The use of well characterized primary immune cells in combination with flow cytometry and other techniques such as ELISA can result in the availability of a robust and easy to implement screening and release assay. Additionally, these assays are also a valuable tool in elucidating the mechanism underlying for example Stem Cell immunomodulatory functions.

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2:00
3D Cell Screening Assays Using Automated Microinjection
 
Jan Sonneville
Jan de Sonneville
CEO
Life Science Methods B.V.
About Speaker: Born on 14-09-1980 in Amsterdam, the Netherlands. Bachelor in Electrical Engineering, Delft University of Technology (TUDelft), Master in NanoScience (Applied Physics), given as joint program by TUDelft and Leiden University, the Netherlands (2006). ... Read Full Bio 
 
 
Jan de Sonneville
CEO
Life Science Methods B.V.
 
About Speaker:

Born on 14-09-1980 in Amsterdam, the Netherlands. Bachelor in Electrical Engineering, Delft University of Technology (TUDelft), Master in NanoScience (Applied Physics), given as joint program by TUDelft and Leiden University, the Netherlands (2006). PhD on the development of four novel research methods for Cell Biology, thesis title: Reinventing microinjection, new microfluidic methods for cell biology (2011). Founded Life Science Methods BV to sell Automated Microinjection Systems for high throughput screening using cell spheroids and zebrafish embryos (2011).

 
Abstract: Using an automated injection robot, we inject tiny droplets of cells into a hydrogel. With this system, we performed a screen of com...Read More 
  • Using an automated injection robot, we inject tiny droplets of cells into a hydrogel.
  • With this system, we performed a screen of compounds that affect breast cancer cell migration, and demonstrated speed, reproducibility, and compatibility with existing lab equipment and techniques.
  • In another screen, we found a correlation of prostate cancer cell migration patterns with metastasis in a mouse model, as well as a dosage dependent effect of a new kinase inhibitor. This kinase was also shown to be expressed in patient tissue.
  • Cell-cell and cell-matrix interactions have been studied by injecting two different cell types next to each other in the same gel, paving the way towards more complex biological models.
  • Currently, we are exploring interactions between immune cells and cancer cells, and immune cells and cells with a bacterial infection.
  • The principle of injecting droplets of cells into precisely predefined spots in a matrix offers many possible applications that I would love to discuss.
  • We can 3D print any tissue of interest. As such our niche is quite broad, especially compared to other competing 3D tissue systems.
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2:25
Monitoring Cleavage Towards and at the Cell Surface for the Enhancement of Drug discovery
 
Roland Wolkowicz
Roland Wolkowicz
Professor, Director of the FACS Facility
San Diego State University
About Speaker: Roland Wolkowicz, Ph.D. is a Professor in Biology at San Diego State University in SD, CA. Born in Barcelona, Spain, he pursued undergraduate research in Biology at the University of Tel Aviv, Israel. Obtained his MSc in Microbiology from Tel Aviv Un... Read Full Bio 
 
 
Roland Wolkowicz
Professor, Director of the FACS Facility
San Diego State University
 
About Speaker:

Roland Wolkowicz, Ph.D. is a Professor in Biology at San Diego State University in SD, CA. Born in Barcelona, Spain, he pursued undergraduate research in Biology at the University of Tel Aviv, Israel. Obtained his MSc in Microbiology from Tel Aviv University, and PhD in Molecular Cell Biology from the Weizmann Institute of Science in Rehovot, Israel, where he studied the p53 DNA binding activity. As a postdoctoral fellow at Stanford University, he became acquainted with retroviral technology, peptide libraries and flow cytometry-based biological screenings. As a research associate at Stanford, he studied novel ways to block HIV-1 infection. In 2006, he joined the Department of Biology at San Diego State University, where he also serves as the Director of the FACS Core facility. His laboratory investigates viral-host interactions, focusing mainly on HIV-1 and Flaviviridae members such as HCV, Dengue virus, West Nile virus and Zika. His laboratory studies the effect of infection on host signaling cascades, and develops cell-based assays that monitor proteolytic cleavage for drug discovery.

 
Abstract: Proteolysis is an essential biological process utilized, among many others, for protein activation, degradation of aggregates, and regulation of si...Read More 

Proteolysis is an essential biological process utilized, among many others, for protein activation, degradation of aggregates, and regulation of signaling cascades. Many proteolytic events occur within the vesicles of the secretory pathway, comprising the Endoplasmic Reticulum, Golgi and trans-Golgi Network (ER/Golgi/TGN) that link the nucleus to the cellular membrane. Monitoring cleavage within the classical secretory pathway or at the cell surface in a biologically relevant background can enhance drug discovery efforts against less obvious targets. These targets include the HIV-1 envelope or premature membrane protein (prM) of Dengue virus (DenV), cleaved within the Golgi/TGN by Furin (or similar), or matrix metalloproteinases such as MMP-14, overexpressed in some cellular transformations and metastasis and active at the cell surface or extracellular matrix. We have previously developed an assay that monitors cleavage of the gp120/gp41 HIV-1 envelope boundary, which was then adapted to the DenV prM boundary and used in a pilot screen in search for inhibitors/competitors of prM cleavage. As proteins such as MMP-14 exploit the same secretory pathway for their own activation and for their transport to the surface, we decided to further adapt the assay to specifically monitor cleavage at the cell surface rather than in its route to the surface. The original assay was based on an engineered protein embedded into the ER membrane consisting of a two-tag system flanking the DenV prM boundary substrate. The assay could distinguish between cleaved and non-cleaved events based on classical flow cytometry. An optimized substrate of MMP-14 was then used as a proof-of-principle to monitor cleavage by MMP-14 at the cell surface. Constitutive/inducible MMP-14 overexpression showed cleavage of the substrate. Preliminary mixing experiments of cells expressing the substrate with cell expressing MMP-14 corroborated that cleavage specifically occurred at the cell surface. This novel platform represents a powerful tool for the search of inhibitors/competitors of MMP-14 substrate recognition/cleavage and is easily adaptable to any substrate cleaved at this cellular location. Benefits: – Cell-based assays that monitor cleavage at the cell surface are limited. – Assay monitors cleavage in the cellular compartment where it naturally occurs. – Adaptable to multiplexed format. – Adaptable to 96 and 384 well-plate for HTS in a robust and stable cell line.

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2:50
Afternoon Networking Break
Joint Session: High Throughput and High Content Screening Assays
Michael Mancini, Baylor College of Medicine
3:20
Phenotypic 3D Imaging of Living Biopsies for Cancer Chemoresistance Screening
 
David Nolte
David Nolte
Distinguished Professor, Physics
Purdue University
About Speaker: David D. Nolte is the Edward M Purcell Distinguished Professor of Physics and Astronomy at Purdue University performing research in the fields of optical technologies for molecular diagnostics and cancer therapeutics. He received his baccalaureate fr... Read Full Bio 
 
 
David Nolte
Distinguished Professor, Physics
Purdue University
 
About Speaker:

David D. Nolte is the Edward M Purcell Distinguished Professor of Physics and Astronomy at Purdue University performing research in the fields of optical technologies for molecular diagnostics and cancer therapeutics. He received his baccalaureate from Cornell University in 1981, his PhD from the University of California at Berkeley in 1988, and was a post-doctoral member of AT&T Bell Labs before joining the physics faculty at Purdue. He has been elected Fellow of the Optical Society of America, Fellow of the American Physical Society and Fellow of the AAAS. In 2005 he received the Herbert Newby McCoy Award of Purdue University. He has founded two biotech startup companies in the area of diagnostic screening and high-content analysis.

 
Abstract: Three-dimensional cancer biopsies from patients are imaged using biodynamic imaging based on laser ranging and Doppler frequency spectroscopy. The ...Read More 

Three-dimensional cancer biopsies from patients are imaged using biodynamic imaging based on laser ranging and Doppler frequency spectroscopy. The response of the living biopsy samples to applied therapeutics is captured as shifts in the biodynamic spectra, presenting specific resistant or sensitive phenotypes. This phenotypic screen captures the physiological response of the tissue to the therapy without the need for genetic profiling. Several therapy candidates can be screened simultaneously, providing oncologists with information on best response for individual patients. This aid to therapy selection can help bring personalized cancer care closer to practice.

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3:45
Single Cell Analysis of Steroid Receptor Functions by HCA
 
Michael Mancini
Michael A. Mancini
Professor
Baylor College of Medicine
About Speaker: ... Read Full Bio 
 
 
Michael A. Mancini
Professor
Baylor College of Medicine
 
About Speaker:
 
Abstract: The main focus of our research has been to identify, characterize and quantify mechanistic steps of steroid nuclear receptor action at the single c...Read More 

The main focus of our research has been to identify, characterize and quantify mechanistic steps of steroid nuclear receptor action at the single cell level by using state-of-the-art microscopy based approaches. To this end, we created stable cell lines and automated image analysis routines that facilitate multi-parametric small molecule screens to identify estrogen and androgen receptor effectors, RNAi libraries for pathway analysis, and also endocrine disruptor compound (EDC) screening. These efforts have led to the creation of biological response fingerprints that identify mechanistic and phenotypic changes in biosensor and native cell lines in response to various treatments. We have also identified novel, disease relevant estrogen receptor coregulators (i.e. UBR5) and receptor-specific EDCs (Bisphenol A analogs). These recent efforts are leading towards an improved understanding of steroid receptor and coregulator action in prostate and breast cancer models.

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4:10
Unfolding the Unfolded Protein Response
 
Chris Wilson
Chris Wilson
Associate Director
Small Molecule Discovery Center, UCSF
About Speaker: Chris Wilson is Associate Director of screening at the Small Molecule Discovery Center, UCSF Mission Bay,. He was previously a Senior Scientist at Ensemble Therapeutics (Cambridge, MA) and a postdoctoral fellow at Yale University, in the protein engi... Read Full Bio 
 
 
Chris Wilson
Associate Director
Small Molecule Discovery Center, UCSF
 
About Speaker:

Chris Wilson is Associate Director of screening at the Small Molecule Discovery Center, UCSF Mission Bay,. He was previously a Senior Scientist at Ensemble Therapeutics (Cambridge, MA) and a postdoctoral fellow at Yale University, in the protein engineering group of Prof. Lynne Regan.

 
Abstract: The Small Molecule Discovery Center (SMDC) at UCSF couples a broad technology base, with a highly collaborative philosophy, to tackle novel screens...Read More 

The Small Molecule Discovery Center (SMDC) at UCSF couples a broad technology base, with a highly collaborative philosophy, to tackle novel screens against challenging targets and biological pathways. Through transcriptional and translational reporter approaches, three independent branches of the Unfolded Protein Response (UPR) were probed, each serving as mutual counter-screens in hit selection. Subsequent medicinal chemistry and animal studies have revealed the potential of the UPR in modulating disease.

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Joint Session: Stem Cell Based Screening Assays
Michael Mancini, Baylor College of Medicine
4:35
Phenotypic Screening of Human Induced Pluripotent Stem Cell (hiPSC) Derived Neuronal Networks On Multi-Electrode Arrays
 
Anne Bang
Anne Bang
Director, Cell Biology
Sanford Burnham Prebys Medical Discovery Institute
About Speaker: Anne Bang joined the Sanford Burnham Prebys in June 2010 as Director of Cell Biology at the Conrad Prebys Center for Chemical Genomics, a state-of-the-art drug discovery center. Her efforts there are directed at developing patient-specific, and human... Read Full Bio 
 
 
Anne Bang
Director, Cell Biology
Sanford Burnham Prebys Medical Discovery Institute
 
About Speaker:

Anne Bang joined the Sanford Burnham Prebys in June 2010 as Director of Cell Biology at the Conrad Prebys Center for Chemical Genomics, a state-of-the-art drug discovery center. Her efforts there are directed at developing patient-specific, and human induced pluripotent stem cell (hiPSC)-based models that reflect higher order cellular functions and disease phenotypes, yet have the throughput and reproducibility required for drug discovery and target identification. Prior to joining SBP she was at ViaCyte Inc. where, as Director of Stem Cell Research, she managed an interdisciplinary group of scientists working to develop hESC as a replenishable source of pancreatic cells for the treatment of diabetes. Dr. Bang has over 20 years of experience in the fields of developmental and stem cell biology, with a focus on neural development. She received a B.S. from Stanford, a Ph.D. in Biology from UCSD, and was a post-doctoral fellow at the Salk Institute.

 
Abstract: Human induced pluripotent stem cells (hiPSC) could aid in the development of clinically useful compounds. They allow interrogation of differentiate...Read More 

Human induced pluripotent stem cells (hiPSC) could aid in the development of clinically useful compounds. They allow interrogation of differentiated features of human cells, circumvent issues of species specificity, and importantly, carry disease-specific traits in complex genetic backgrounds that can impact disease phenotypes. Development of patient specific hiPSC based models to study the cellular and molecular bases of neurological disease offers an opportunity to identify improved treatments, and to better stratify patients according to pathological processes. The biology and genetics underlying neurological disease are complex and will require the examination of multiple cell types from many patient hiPSC lines to identify and validate phenotypes. Development of procedures to interrogate hiPSC derived neural cells in miniaturized higher-throughput formats will be advantageous not only for drug screening, but also for phenotype discovery, allowing testing of multiple lines and variables, such as timing and dose response to therapeutic agents, pathway modulators, and stress inducers. Using hiPSC-derived neurons, we have developed a functional assay on 48 and 96 multi-well multi-electrode array (MEA) plates that recapitulates physiologically relevant synchronized bursting properties sensitive to shifts in the balance of excitation and inhibition. Advantages of this system include throughput, and the ability to non-invasively measure networked neuronal activity over days and months. We will discuss use of this assay for compound screening and modeling of synaptic plasticity and neurological disease.

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5:00
Conference Concludes