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Part ofOctober 13-16, 2009
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This conference will feature presentations and case studies of how leading companies are using broader and deeper understanding of Mechanism of Action to drive new Pipeline Value. Join leading practitioners to learn the latest biophysical and cellular methods for studying Mechanisms of Action. Learn how to:
Scientific Advisory Committee:
Robert A. Copeland, Ph.D., Executive Vice President & Chief Scientific Officer, Epizyme, Inc.
Aaron Schimmer, M.D., Ph.D., FRCPC, Staff Physician and Scientist, Princess Margaret Hospital, Ontario Cancer Institute; Assistant Professor, Departments of Medicine and Medical Biophysics, University of Toronto
Rumin Zhang, Ph.D., Senior Principal Scientist, New Lead Discovery, Schering-Plough Research Institute
DAY ONE: THURSDAY, OCTOBER 15, 2009
7:30 am Registration and Morning Coffee
Biophysical Methods forStudying Mechanism of Action
8:30 Chairperson’s Opening Remarks
David Swinney, Ph.D., Director, Biochemical Pharmacology, Roche Palo Alto
8:40 Drug-Target Residence Time: An Alternative Approach to Compound Optimization
Much of drug discovery today is predicated on the concept of selective targeting of bioactive macromolecules by small molecular weight drugs or by biopharmaceutical drugs. Hence, binding of drugs to their macromolecular targets is seen as paramount for pharmacological activity. Assessment of drug-target interactions is classically quantified in terms of binding parameters such as the IC50 or Kd. An alternative perspective on the in vitro assessment of drug optimization is presented here, in terms of drug-target residence time, as quantified by the dissociative half-life of the drug-target binary complex. In most cases a long residence time of the drug-target complex results in an extended duration of pharmacodynamic activity, even when systemic concentrations of drug have been significantly reduced through metabolism and other elimination routes. Hence, long residence time for a drug at its biomolecular target can enhance the duration of drug efficacy in vivo and can also significantly diminish the potential for off-target-mediated toxicities. Examples of how these concepts can be incorporated into compound optimization efforts will be presented.
9:10 The Role of MoA in Therapeutically Useful Drug Action
Binding mechanism (MoA) and binding kinetics help define how a medicine communicates with physiology to produce a therapeutic response. MoA and binding kinetics can influence clinical efficacy, safety, duration of action and differentiate medicines. Early identification of an optimal MoA may reduce attrition rates due to maximization of the therapeutic index. The value of MoA to drug discovery will increase through an improved ability to identify optimal MoAs and define corresponding structure activity relationships.
9:40 Identifying the Proteins to which Small-Molecule Probes and Drugs Bind in Cells
Shao-En Ong, Ph.D., Research Scientist II, Proteomics, Broad Institute
10:10 Networking Coffee Break with Exhibit and Poster Viewing
Cellular Methodologies forUnderstanding Mechanism of Action
10:50 Using RNAi Screens in Determining Mechanism of Action - Velcade in Myeloma
Rodger E. Tiedemann, M.D., Ph.D., FRACP, FRCPA, Assistant Professor of Medicine, Division of Hematology Oncology, Mayo Clinic
We have conducted a high-throughput (13,984-oligo; 6,791 gene) small interfering RNA (siRNA) lethality screen in human myeloma cells to identify and map vulnerabilities in the ‘druggable genome’ of myeloma cells. Concurrent siRNA studies were performed in cells treated with sub-lethal or lethal doses of bortezomib to identify molecular targets whose inhibition induces chemo-sensitization to, or protection from, proteasome inhibition. We have validated 30+ highly vulnerable targets essential for Myeloma cell survival and additional targets that modulate sensitivity to bortezomib, informing on mechanism of action and suggesting novel treatment approaches and enhanced drug combination strategies.
11:20 Sponsored Presentation (Opportunities Available)
11:50 Lunch Presentation (Opportunity Available) or Lunch on Own
Case Studies in Applying Mechanism of Actionfor Drug Discovery and Development
1:25 pm Chairperson’s Remarks
1:30 Impact of Drug-Enzyme Target Residence Time on the Development of Novel Cancer Therapeutics
Peter J. Tummino, Ph.D., Senior Director, Biology, Oncology Research & Development, GlaxoSmithKline Pharmaceuticals
The improvement of drug-target potency, as typically quantified by IC50 or Ki, is considered an essential component for the optimization of small molecule inhibitors into pharmacological agents. An additional parameter to quantify the drug-target binding that is critically important for drug optimization is the drug-target residence time, or the dissociative half-life for the drug-target binary complex. In our drug discovery efforts, we have observed that candidate drug molecules often possess long drug-target residence times and that this can result in more potent and durable drug activity in cells and in vivo, and improved drug selectivity. Drug-target residence time is also an important parameter to more fully interpret inhibitor structure-activity relationships. Examples will be presented from our efforts to develop novel cancer therapeutics against epidermal growth factor receptor (EGFR), heat shock protein 90 (Hsp90), kinesin motor protein, and aurora kinase.
2:05 Systematic Combination Screening for Multi-target Mechanisms
Margaret Lee, Ph.D., Vice President, Therapeutic Area Research, CombinatoRx
High-throughput combination screening allows the systematic evaluation of combi nations of approved drugs and molecularly targeted agents in panels of cell based assays representing the complex biology and genetics of disease. This approach enables insight into the biological mechanism of action of drug combinations and the discovery of novel therapeutic applications. Using this approach, we have discovered two novel and related classes of drug targets with highly synergistic and selective anti-tumor activity in several pre-clinical models of MM. The work presented will describe a compelling and proven technology enabling the discovery of new biological insights into the mechanism of action of known drugs and targets and for the identification of unexpected mechanistic interactions. A case study will be presented that demonstrates the utility of this approach and describes two novel targets that have been validated in pre-clinical models of Multiple Myeloma.
2:45 Networking Refreshment Break with Exhibit and Poster Viewing
3:30 Mechanism of Action and Cytoprotection: New Uses for Acetaminophen
Gary F. Merrill, Ph.D., Professor, Cell Biology and Neuroscience, Rutgers University
Acetaminophen has a long-standing history of efficacy and safety. It is safe, inexpensive and there is growing basic evidence to support the pursuit of new therapeutic uses for this compound. Mechanism of action studies of acetaminophen and its potential cardioprotective and neuroprotective properties will be reviewed. Because of these qualities, new uses for this old drug should be pursued. A pharmaceutical/academic consortium to promote such investigation would be useful.
4:10 Utilization of the theraTRACE® in vivo Profiling Platform for Uncovering New Biological Function for Molecular Targets
Michael Saporito, Ph.D., Co-founder and Vice President, Research, Melior Discovery, Inc.
Melior Discovery identifies novel indications for pre-clinical and discontinued clinical stage drug candidates by employing a multi-therapeutic in vivo profiling platform termed theraTRACE®. This approach is driven by in vivo functional activity and can identify new pharmacology and biological function for previously identified molecular targets. This presentation will describe the theraTRACE® approach with a specific focus on an example of new pharmacology for a previously discontinued compound that was uncovered using this multi-therapeutic screen. In addition, this presentation will highlight the new biological function associated with this previously identified molecular target. We will examine the power of in vivo biological systems for fully profiling the therapeutic potential of a pharmacological agent and explore the potential range of functional activities of a molecular target.
4:50 Close of Day One
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