Overview

Friday, October 21

8:00-8:30 Registration and Morning Coffee

Biology-Based Screening Strategies

8:30-8:40 Chairperson's Remarks
TBA

9:10-9:40 Tools and Strategies for Chemical Annotation of Biology
Doug Auld, Ph.D., Group Leader, Genomic Assay Technologies, NIH Chemical Genomics Center
New tools and technologies will be necessary to understand the biology of the human genome. Small molecules provide a complementary tool to the currently available nucleic acid-based tools such as siRNA. The drug discovery industry routinely uses small molecules to modulate receptor and enzyme function in many systems. However, the ability to routinely identify biologically active small molecules has not been made widely available to public sector science. The National Institutes of Health Chemical Genomics Center is focused on the use of small molecule chemical libraries coupled with industrial-scale high-throughput screening against diverse areas of biology to provide the broader research community with useful chemical probes. An overview of the current assays, strategies and technologies ongoing within this center will be given.

9:40-10:10 Discovery and Optimization of Highly Selective Hsp90 Inhibitors Using Chemoproteomics
Dr. James Veal, Director Informatics & Structural Chemistry, Informatics & Structural Chemistry, Serenex Inc
Novel Hsp90 inhibitors were identified in a chemoproteomics screen of a focused small molecule library. The same Proteome Mining assay allowed us to rapidly progress the initial hits into a highly selective Hsp90 inhibitor series with in vivo efficacy in a number of human tumor xenograft models.

10:10-10:30 Coffee Break

10:30-11:00 Biology-Based Screening Strategy: A Successful Approach to Hit Identification
Megan Murphy, Ph.D., Scientist, Chemistry, AstraZeneca Pharmaceuticals
We have pursued screening sets of compounds previously associated with biological activity, not necessarily to the target of interest. The hit rates for this approach are higher than those for many target-focused libraries. The rationale and advantages of the biology-based screening strategy will be discussed.

11:00-11:30 Signature-Based Approaches to Small Molecule Library Screening
Kimberly Stegmaier, M.D., Instructor in Pediatrics, Pediatric Oncology, Dana-Farber Cancer Institute
The ability to identify new modulators of malignancy has been restricted to two main approaches to small molecule library screening: target-based and phenotype-based. Each approach has its own limitations. Often, the target of a biological process is unknown, and complex phenotypes can be difficult to assay. We developed a chemical genomic approach to screening, gene expression-based high-throughput screening (GE-HTS), in which a gene expression signature serves as a surrogate for different biological states. This method is an entirely generic system and can be applied to a multitude of small molecule screens. In an era of genomic technology, it is now feasible to envision a generic platform of small molecule library screening in the absence of molecular understanding of a disease, enabling the systematic exploration of diseases not previously studied.

11:30-12:00 Target or Drug-Like Molecule First? 
Dr. Andrew Hopkins, Associate Research Fellow, Knowledge Discovery, Pfizer Global R&D
There has been a tendency to fit the drug discovery process around new technologies, whereas learnings from the origin of "first in class" New Molecular Entities could suggest the technology should be made to work in a different way. Having "drug-like" molecules at the front end of the drug discovery process and systematically target and disease hopping, thereby using "Drug Prototype Driven Drug Discovery" in a complementary manner to the now routine "Target Driven Drug Discovery," might improve productivity.

12:00-12:15 Technology Watch

12:15-1:30 Lunch and Learn Workshop or Lunch on Your Own (Sponsorship available) 

1:30-1:35 Chairperson's Remarks

1:35-2:05 Transcriptional Profiling in Small Molecule Drug Discovery
Helen Brady, Ph.D., Group Leader, Discovery Research, Celgene
Global gene expression analysis (high-density gene array) has become a standard tool in early discovery research such as target discovery and validation in the pharmaceutical industry. This technology is also being applied further down the drug discovery process to help optimize potential small molecule drug candidates using cell-based assays in the preclinical setting. This presentation will focus on the application of gene expression analysis to small molecules. Case studies and examples will be presented on small molecule modulators (with known and unknown mechanisms), highlighting the use of gene expression profiles to categorize compounds and gain understanding of compound mechanism of action. In addition, the use of these methods to evaluate effects of compounds on specific pathways and potentially identify new therapeutic utilities for a compound will be addressed.

Small Molecule Tools for Target Validation

2:05-2:35 Protein Kinase Target Evaluation through Chemogenomics
Paul Caron, Ph.D., Senior Research Fellow, Head of Informatics, Vertex Pharmaceuticals
This presentation will show how data from enzymological and cellular assays can be analyzed in new ways to set criteria for potency and selectivity of kinase inhibitors. In addition, this new methodology addresses the critical challenge of validating targets using imperfect (non-selective) chemical tools rather than biological tools. Using this method has allowed novel insights into the links between specific targets and their physiological effects to be surmised using the sort of non-optimized compounds which are generally available at the outset of a project.

2:35-3:05 Validation of Cellular Signaling Targets Using B Gal Enzyme Fragment Complementation (EFC)
Keith Olson, Ph.D., Director, Marketing, DiscoveRx Corp
B gal EFC is a powerful technology that allows validation of several targets involved in cell signaling. The presentation discusses recent applications of the technique to the use of RNAi studies and to various assay approaches used in cell pathway analysis.

3:05-3:20 Networking Refreshment Break

3:20-3:50 In vitro and In vivo Target Validation Using Selective and Spectrum Selective Inhibitors of PTEN Pathway Components
David Matthews, Ph.D., Senior Director, Discovery, Exelixis
We have used small molecule inhibitors of signaling kinases downstream of PI3K to characterize the in vitro and in vivo consequences of blocking the pathway at different points. This information was used to guide the optimization of inhibitors that target multiple kinases in pathway. These compounds have both a novel molecular profile and encouraging in vivo anti-tumor effects.

3:50-4:20 Exploring Compound Activities Through Pathway Analysis of Expression Profiling Data
Dr. Petra Ross-MacDonald, Senior Research Investigator, Applied Genomics, Bristol Myers Squibb Co

4:20-5:00 Chairperson’s Conference Wrap-Up

For Sponsorship and Exhibit Opportunities
John Yurewicz, Manager of Business Development
Phone: 617.630.1383, Cell: 857-636-8188 • Email: jyurewicz@healthtech.com