5:00-6:00 pm Early Registration


Monday, June 28

8:00 am Registration, Poster Setup and Coffee

Compound-Centric Information

8:45 Chair’s Opening Remarks

8:50 Drug Development and the Application of Compound Centric Strategies
Dr. Phil Edwards, Principal Scientist II, Chemistry, AstraZeneca Pharmaceuticals, Inc.
The development of combinatorial chemistry and HTS has enabled the screening of large libraries(>1M) in the search for leads to initiate drug discovery programs. These efforts are expected to increase the rate of hit identification by "taking more shots on goal" More recently, however, it has come to be appreciated that small libraries composed of diverse, biology-rich compounds, may afford leads with greater value and knowledge content. This presentation will describe the value and design of biology annotated libraries, and provide a case study as to how such libraries can be used for black-box assay deconvolution, target identification, and small molecule lead generation.

9:20 Learning From History: Tapping 50 Years of Medicinal Chemistry Experience
Dr. Mark Murcko, Chief Technology Officer and Chair, Scientific Advisory Board, Vertex Pharmaceuticals, Inc.
Medicinal chemists can tap their experience and their knowledge of the literature to make educated predictions about the properties of molecules. However, no chemist, no matter how experienced, has more than a tiny fraction of the world’s chemical knowledge at their fingertips. Proprietary databases have been constructed that contain curated information about molecules of interest to medicinal chemists — their target activities, physical and ADME properties, commercial availability, patent status, and so on. We have also developed proprietary tools to help the chemists query and analyze these databases. Some of the ways in which these informational resources are being used at Vertex will be presented.

9:55 Poster and Exhibit Viewing and Coffee Break

10:45 A Chemogenomic Approach using Annotated Compounds
Dr. Paul Clemons, Head of Systematic Chemical Genetics, Institute of Chemistry & Cell Biology, Harvard University
Our one-bead, one-stock solution approach to chemical genetics (Chem.Biol. 8: 1167-1195) is a technology platform capable of delivering thousands of novel small molecules, prepared by diversity-oriented organic synthesis (DOS), to hundreds of diverse biological assays. Applying principles of multidimensional data analysis reminiscent of genomics, we have begun systematically to explore the relationships between chemical structure and perturbations of intact biological networks. We have undertaken an experimental strategy, termed library annotation, designed to generate phenotypic “fingerprints” for novel small molecules using cell-based assays.

11:15 SafeBase™ — A New in silico Platform for Drug Profiling
Dr. Felix Frueh, Head of US Operations, TheraSTrat AG
Despite improving methods to characterize and prioritize novel drug candidates early in the development process, the main reason for post-market drug withdrawals remains the likelihood of the compounds to instigate adverse drug reactions (ADRs). By integrating structures of parent compounds, such as new drug candidates, with metabolites and their metabolic pathways, covalent adducts, pharmaco-, and toxicokinetic and -dynamic data, proteomic information, genetic variations, gene expression levels, as well as clinical outcome data, we have created a novel database for use in this application. This flexible and searchable knowledge base, SafeBase™, allows effective prioritization and optimization of lead compounds, supports the assessment of drug safety and efficacy, helps identifying the mechanisms of drug action, and assists in the identification of risk factors responsible for predispositions of ADRs.

11:45 Panel Discussion

12:15 Lunch on your own
(Technology Workshop Sponsorship Available)
 

Compound Efficacy and Selectivity

1:45 Chair’s Remarks

1:50 Clustering of Multi Targeted Kinase Inhibitors using Gene Expression Profiling and Biochemical Assay Data
Dr Timothy Perera, Principal Scientist, Johnson & Johnson Pharmaceutical Research and Development
Unsupervised clustering algorithms that group compounds based on gene expression profiling and kinase inhibition data have been developed. The use of these tools in the prioritisation of novel Oncology drug candidates for therapeutic intervention will be presented.

2:20 Use of Laser Capture Microdissection and Expression Profiling for CNS Applications
Dr. Holger Hiemisch, Director of Neuroscience, Axaron Bioscience AG
A significant obstacle for the successful application of gene expression profiling is the complexity of the tissues and organs to be analyzed. Cell type specific regulatory events, often crucial for understanding a disease process or drug action, can be hidden by the noise generated by irrelevant cells which often represent the majority in a complex tissue. Case studies from mode of action experiments and toxicity studies based on Axaminer, a technology for cell type specific transcription profiling comprising four modules; cell-type labeling, automated laser microdissection, RNA amplification and microarray analysis, will demonstrate the advantages of performing gene expression profiling at the cellular level.

2:50 Applying Molecular Signatures to Evaluate Drug Mode of Action, Selectivity, New Animal Models and Novel Indications
Dr. David Bol, Senior Scientific Director, Applications Biology, Avalon Pharmaceuticals, Inc.
Molecular signatures are being used to describe the effects of compounds on cells. Using a number of analysis tools, as well as comparing compound transcriptional activities to hundreds of compounds with reported anticancer activity, we have been able to show differences between compounds of interest that represent novel mechanisms of action, selectivity, mode of action, and off target effects. Additionally, we have been able to use the genes responding to a specific set of compounds to help develop new animal models, and identify potential new indications within the cancer field for those compounds.

3:20 Poster and Exhibit Viewing and Refreshment Break

4:00 Using Genomic and Proteomic Profiling for Selectivity Assessment
Dr. Yan Luo, Senior Group Leader, Abbott Laboratories
Conventional assessments of compound selectivity are often limited to particular classes of closely related target proteins, which is often misleading in decision making. In contrast, genomic and proteomic tools provide a physiological, as well as a thorough and unbiased snapshot of compound’s effect and often reveal unexpected non-selectivity. Maximal efficacy may call for a optimal combination of non-selectivity as opposed to pure selectivity.

4:30 Assessing Selectivity using Expression Profiling
Dr. Petra Ross-Macdonald, Senior Research Investigator, Applied Genomics, Bristol-Myers Squibb
A major aspect of candidate prioritization involves triage of compounds that have liabilities of selectivity. We are analyzing the gene expression profiles of treated cells to uncover differences in activity, providing a novel means of characterizing compounds for prioritization. Early experience with implementation of this approach on several programs will be discussed.

5:00 Chemo-Proteomics to Profile Kinase Inhibitor Selectivity
Dr. Bert Pronk, Director, Biology, Serenex
Now that the sequencing of the human genome has revealed all potential kinase tartgets, the question of compound selectivity of kinase inhibitors has become even more daring to address. Moreover, since most kinase inhibitors are competing for ATP binding, true selectivity needs to be addressed in an even broader panel of ATP-binding proteins. With our proprietary affinity resins we can potentially capture all ATP-binding proteins, and thus address compound selectivity against a large panel of potential targets. This Proteome Mining technology is also being applied to guide lead optimization, and examples will be shown where minor changes in a molecule dramatically change selectivity profiles. Further, we have profiled a library of over 8000 putative ATP competitive compounds using Proteome Mining, and we are currently following up on compounds that show interesting target selectivity or target profiles.

5:30 Panel Discussion

6:00 Networking Reception

7:00 Close of First Day