2:00 Chairperson: James K. Chen, Ph.D., Assistant Professor, Department of Molecular Pharmacology, Stanford University School of Medicine

2:05 Building Robust Chemical Genomic Databases Using Concentration-Response-Based Screening of Large Chemical Libraries
Doug Auld, Ph.D., Group Leader, Genomic Assay Technologies, NIH, Chemical Genomics Center
The National Institute of Health Chemical Genomics Center (NCGC) is focused on the use of small molecule chemical libraries coupled with ultra-high-throughput screening against diverse areas of biology to develop chemical probes for the study of protein and cell functions. The NCGC has developed a process called “quantitative HTS” (qHTS) that allows large chemical libraries (100K) to be screened as a concentration-titration series. This lecture will cover the use of this data for both identifying chemical probes as well as constructing a publicly available database that relates chemical structure to biological function. This process also provides a platform to accelerate the identification of leads for biomedical research.

2:35 Using Genomic Response As Systems Biology Approach To Improve Drug Discovery And Development
Kenneth C. Carter, Ph.D., President and CEO, Avalon Pharmaceuticals
We have developed a fully integrated systems biology technology for drug discovery and development, AvalonRx, that provides comprehensive measurements of gene expression that reflect changes in complex control mechanisms and pathways. In our current clinical trial with our lead drug candidate, AVN944 – potent and novel anti-cancer compound, we are using our technology to monitor a wide range of cellular activities that should provide biomarkers that will guide patient stratification, dosing, combination therapy choices and other key aspects of future clinical trial designs. AvalonRx also provides a unique approach for drug screening and allows for targeting pathways that are traditionally thought of as undrugable and provides advantages even in case of traditional targets. We have several discovery programs using this approach, the most advanced of which target the ß-catenin and Aurora pathways.

3:05 From Compound to Target: Old Dilemma, New Technologies
Donald G. Jackson, Ph.D., Senior Research Investigator, Applied Genomics, Bristol-Myers Squibb
Although we are in an era of target-based drug discovery, off-target effects continue to generate situations where it’s important to find all the relevant molecular targets for a compound. This process of identification has always been difficult and labor intensive, but new technologies such as Expression profiling, high-content screening and reverse genetics could help. A case study using these approaches to identify the mechanism and target of a novel cytotoxic compound will be presented.

3:35 Networking Refreshment Break

4:00 Chairperson: Nathanael S. Gray, Ph.D., Assistant Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana Farber Cancer Institute

4:00 Accelerating Kinase Inhibitor Discovery through Selectivity Profiling
Patrick Zarrinkar, Ph.D., Senior Director, Technology Development & Alliance Management, Ambit Biosciences, Inc.
Selectivity is an important issue that must be addressed if kinase inhibitors are to be used as chemogenomics tools. To systematically explore selectivity, we have applied a novel competition binding assay to profile a wide variety of known kinase inhibitors against a panel of more than 225 protein kinases. To guide and accelerate discovery of new inhibitors, we have further exploited the efficient and broad screening capability afforded by the new assay to profile entire compound libraries, as well as all compounds synthesized during the optimization of initial screening hits, against the kinase panel. This approach immediately reveals which targets can be accessed with available compounds and facilitates decisions about which targets and compound series to pursue. Our strategy has enabled the rapid development of highly potent and selective inhibitors of class III receptor tyrosine kinases.

4:30 Multi-Dimensional Chemical Genetics Application to Producing Multi-Component Therapies
Glenn Short, Ph.D., Senior Scientist, Technology & Platform Development, CombinatoRx Inc.
Increased understanding of the complexity of biological networks is forcing us to reconsider traditional views of disease and treatment. There is now widespread recognition that coordinated action at multiple molecular targets may provide unique therapeutic benefit not achievable with the “one-drug, one-target” paradigm. Forward chemical genetic screens have traditionally been used to identify individual compounds that effect phenotypic changes via single molecular targets. One limitation of this approach is that a compound may inhibit a disease-relevant cellular process, yet produce no phenotype in isolation due to a compensatory response by the system. We have developed cHTS, a multi-dimensional chemical genetic method that identifies synergistic combinations of compounds that act at multiple points within cellular networks. These combinations can reveal previously unappreciated interactions between signaling pathways or genes that would otherwise be missed by traditional discovery methods. We are using cHTS to discover multi-component drugs that act synergistically on disease systems with mechanisms that cannot be achieved by individual compounds.

5:00 RNAi-Based Synthetic-Lethal Screening: A New Approach to Designing Multi-Targeted Kinase Inhibitors 
Joel D. Leverson, Ph.D., Associate Research Investigator, Cancer Research Department, Abbott Laboratories 
Tumors comprise genetically heterogeneous cell populations whose growth and survival depend on multiple kinase signaling pathways. This fact has spurred the development of small molecules that can inhibit multiple kinases. A major challenge is to determine which kinases to inhibit in each cancer to maximize efficacy and therapeutic index. In order to identify kinases that cooperate with Akt to maintain cancer cell survival, we screened a library of kinase-directed small interfering RNAs (siRNAs) for enhanced cancer cell killing in the presence of the Akt inhibitor A-443654. siRNAs targeting casein kinase I gamma 3 (CSNK1G3) or the inositol polyphosphate multikinase (IPMK) significantly enhanced A-443654-mediated cell killing, and caused decreases in Akt Ser-473 and ribosomal protein S6 phosphorylation. Small molecules targeting CSNK1G3 and/or IPMK in addition to Akt may thus exhibit increased efficacy and have the potential for improved therapeutic index. 

5:30 Happy Hour in the Exhibit Hall
Enter to win and iPod® nano!  
Enter at the CHI registration desk. Winner will be announced in the exhibit hall. You must be present to win.*

7:00 Close of Conference Day  

Wednesday, October 25

Shared Program Day with Ion Channels

7:00 am Registration and Morning Coffee

7:30 Breakfast Workshop (Sponsorship Available)

KEYNOTE SESSION

8:30 Keynote Introduction 8:40 Target Discovery: Seeking Innovation and the Role of Collaboration with Biotech and Academia Jeremy Levin, D. Phil, MB. Bchir, Global Head, Business Development and Strategic Alliances, Novartis 9:10 Reducing Clinical Attrition through Efficiencies in Discovery Joseph Bolen, Ph.D., Senior Vice President, Research & Drug Discovery, Millennium Pharmaceuticals

9:40 Coffee Break in the Exhibit Hall

DIFFERENT PERSPECTIVES

10:30 Chairperson: Birgit T. Priest, Ph.D., Senior Research Fellow, Department of Ion Channels, Merck Research Laboratories

 

Featured Speaker

10:30 Genotype-Selective Compounds for Cancer and Neurodegeneration Brent R. Stockwell, Ph.D., Assistant Professor, Department of Biological Sciences and Department of Chemistry, Columbia University We have developed high-throughput cell-based screens that identify small molecules with genotype-selective activity. In one case, we have identified small molecules that are selectively lethal to tumor cells harboring oncogenic RAS. In a second case, we have discovered small molecules that selectively prevent mutant-huntingtin-induced apoptosis. We are using chemical synthesis, affinity purification and mass spectrometry to identify protein targets of such compounds, illuminating mechanisms for achieving such genotype-selective modulation of cell death mechanisms. 11:05 E-VIPR Enables Gene Family Approach to Voltage-gated Ion Channels Jesus “Tito” Gonzalez, Ph.D., Senior Director, Biology, Vertex Pharmaceuticals Voltage-gated ion channels regulate many physiological functions and are targets for numerous drugs. Functional assay methods generally used for these targets included: 1) patch-clamp electrophysiology, which is information-rich but laborious and costly; and 2) membrane potential and flux assays which provide high-throughput analysis but relatively little mechanistic information. Here we discuss an electro-optical technology, E-VIPR, that employs extracellular electrical field stimulation and cellular fluorescent probes to measure the activity of voltage-gated ion channels. We demonstrate advantages of this platform that remove important conventional assay constraints and allow large-scale profiling of selectivity, mechanism of action and kinetics of channel modulators. The robustness, sensitivity and flexibility of this technology has potential to provide unprecedented access to voltage-gated ion channel targets.

 

Featured Presentation

11:40 Using Chemogenomics Approaches for Novel Target Discovery and Compound Mechanism of Action Alex Gaither Ph.D., Research Investigator I, Genome and Proteome Sciences Department, Novartis Institutes for Biomedical Research A three step pipeline has been developed to improve siRNA based target discovery using compounds; an unbiased way to optimize for siRNA delivery into cells, screening small disease relevant subsets of the genome, and incorporating compound treatment as a tool to activate pathways relevant to disease. Using this optimized chemogenomics based approach, combining siRNA and compound screens, we have identified targets that can improve novel and/or preexisting compound therapies. This technology has been systematically applied to many compounds in the pipeline to better understand a small molecule’s activity before moving into the clinic. Chemogenomics provides a way to rapidly assess the value of compounds as therapies through mechanism based siRNA screening.

12:15 Technology Watch (Sponsorship Available)

12:30 Lunch in the Exhibit Hall

Roundtable Buzz Session

2:00  Roundtable: Screening Entire Libraries Verses Focused Libraries Moderator: Alex Gaither Ph.D., Research Investigator I, Genome and Proteome Sciences Department, Novartis Institutes for Biomedical Research Discussion Points  • Redundancy and multiple reagent screening  • Comprehensive coverage of chemotype or siRNA reagent space  • Efforts of validation  Roundtable: “Proving" Selectivity/Confirming Mechanism of Action of Small Molecules Moderator: Steve E. Hall, Ph.D., Senior Vice President, Research and Development, Serenex, Inc. Roundtable: Chemical Probes to Interrogate Physiological Pathways

3:30 Refreshment Break in the Exhibit Hall 

 

ION CHANNELS AND SMALL MOLECULE TARGET DISCOVERY

4:00 Chairperson: Alex Gaither Ph.D., Research Investigator I, Genome and Proteome Sciences Department, Novartis Institutes for Biomedical Research

4:10 Development of Novel TRP Channel Antagonists with Analgesic Properties
Magdalene Moran, Ph.D., Senior Scientist and Director, Target Discovery-Channel Group, Hydra Biosciences
We have investigated the role of a TRP channel and its involvement in the transmission of painful stimuli. In order evaluate the role of this channel, Hydra Biosciences has developed a high throughput screen that allowed the identification of selective antagonists. Importantly, these antagonists are highly selective over voltage-gated channels, such as hERG and other TRP channels including the capsaicin receptor, TRPV1. In vivo assessment showed this class of antagonists to be efficacious in several models of pain. To our knowledge, this represents the first example of a selective antagonist to this TRP channel and validates it as a target for the treatment of inflammatory and nociceptive pain.

4:35 Using Worm Genetics to Identify Small Molecule Targets and the Residues Required for Interaction
Peter J. Roy, Ph.D., Assistant Professor, Department of Medical Genetics and Microbiology, University of Toronto
Identifying the protein targets of small bioactive molecules discovered through phenotypic screens is a major bottleneck of generating useful biological probes. Here, we show how C. elegans mutants that are resistant to a small molecule led to the discovery of a novel L-type calcium channel antagonist with unique properties. In addition, we believe that the mutated residues provide novel insights into channel function and interaction with the antagonist. We propose that this approach will be of similar value for other small molecules that have bioactivity in C. elegans.

5:00 Exploring a Focused Library of Novel Kv Channel Active Compounds
Geoffrey W. Abbott, Ph.D., Assistant Professor, Department of Medicine, Cornell University, Weill Medical College
Voltage-gated potassium (Kv) channels control membrane potential, excitability, and action potential morphology and duration. As such, Kv channels represent ideal candidates for therapeutic intervention to prevent abnormal electrical excitability; conversely, inappropriate pharmacological modulation (or mutation) of these channels can generate broad electrical dysfunction, exemplified by inadvertent inhibition of the hERG potassium channel and acquired long QT syndrome. We are adopting a low-throughput approach to explore novel channel-active compounds in a focused library identified by specifying three simple criteria: a modular, expandable structural platform, net positive charge, and lack of effects on hERG. Surprisingly, different compounds within the same structural class act as Kv channel antagonists or agonists depending on subtle structural differences and channel type. Ongoing studies are aimed at identifying the binding sites of existing compounds while developing new compounds based on the most promising structural sub-classes.

5:30 Close of Conference Day

*Apple is not a sponsor or participant of this program.

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