DCH_KIC_2010

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Wednesday, April 28


12:30 pm Registration


GENERATING NOVEL INHIBITORS

1:30 Chairperson's Opening Remarks

Juswinder Singh, Ph.D., CSO, Avila Therapeutics

1:40 Discovery of Novel JNK Inhibitors for the Treatment of Parkinson’s Disease

Philip LoGrasso, Ph.D., Professor; Senior Director, Molecular Therapeutics, The Scripps Research Institute

c-jun-N-terminal-kinase 3 is (JNK 3) expressed primarily in the brain and is associated with Parkinson’s disease. In this study we developed highly potent, selective JNK inhibitors which had good brain penetration, good DMPK properties, and showed in vivo efficacy in animal models of Parkinson’s disease. Moreover, compounds developed had plasma:brain ratios of 2:1 or even 1:1 with good DMPK properties in rat. Furthermore, these compounds were shown to be efficacious in the 6-OHDA and MPTP animal models of Parkinson’s disease.

2:10 Fragments and Drug Discovery for Kinase Targets

Speaker to be Announced.

2:40 Targeting the Polo-Box Domain of Polo-Like Knase 1 (Plk1)

Kyung Lee, Ph.D., Senior Investigator, Metabolism, National Cancer Institute

Although development of kinase therapeutics has long been sought, the current prevailing strategy of inhibiting the catalytic activity of the kinases has suffered from a high level of cross-reactivity with other unrelated kinases. Protein-protein interaction inhibitors are thought to be highly specific and, therefore, more amenable for combinatorial therapy with less toxicological problems. However, largely due to the difficulty of finding a right target with a small, well-defined, and unique binding cleft has hampered the development of this of therapeutic agents. We have identified a 5 amino acid-long peptide and generated high affinity peptidomimetics that specifically bind to and specifically inhibit the non-catalytic, but functionally essential, polo-box domain of Plk1. Our current effort for the generation of a new of anti-Plk1 PBD inhibitors will be discussed.

3:10 Selected Oral Poster Presentation:

Computational Prediction of Kinase Inhibitor Selectivity Using Homology Modeling and CHARMM-Based Molecular Docking

Roger S. Armen, Ph.D., Research Fellow, Department of Chemistry, University of Michigan

3:25 Networking Refreshment Break, Poster and Exhibit Viewing


TOOLS and PLATFORMS

4:20 “Teflon Phosphates”– Accessible Chemical Biological Tools to Study Kinase-Mediated Phosphorylation Pathways

David B. Berkowitz, Ph.D., Professor of Chemistry, University of Nebraska

Our research group was the first to develop the alpha, alpha-difluoromethylene)phosphonate analogues of pSer, pThr and p-allo-Thr.  These unnatural amino acids (AAs) are phosphatase-resistant, isopolar mimics of the corresponding phosphorylated AAs.  Their incorporation into proteins results therefore in a “constitutively on” phenotype.  Described will be synthetic entries into these “teflon phosphates” and their application to the study of kinase-mediated signal transduction.

4:50 A Novel Platform Based Approach to Silence Kinase Drug Targets Using Covalent Inhibitors

Juswinder Singh, Ph.D., CSO, Avila Therapeutics

Although there are many examples of safe and successful covalent drugs the majority were discovered through serendipity.  We have developed a platform that enables the rapid discovery and optimization of small molecule inhibitors that covalently modify their targets leading to specific and durable silencing of the targeted protein.  We have applied our approach widely and have achieved durable and specific silencing of many important drug in vitro, ex-vivo and in vivo. Importantly, use of covalent drugs affords a unique translational advantage: the ability to monitor target occupancy to inform appropriate dosing.  Our novel and broad approach to drug development should result in drugs with better efficacy, improved specificity and more favorable dosing.  We illustrate our approach with specific examples in the area of cancer and auto-immunity.

5:20 pm Break-Out Discussions

Topic: Interactions between Academia and Industry

Moderator: Michael Soth, Ph.D., Roche

  • what areas of kinase research are better suited for what environments (e.g. drug discovery versus target discovery)
  • how can academics gain access to highly selective inhibitors developed internally by industry and what would industry get out of it
  • what are less well-defined areas of research in which kinase inhibitors could play a role, e.g. stem cell manipulation, and how could academia and industry collaborate on them

Topic: Is specificity all it’s cracked up to be?

Moderator: Jordan Friedman, Ph.D., Director, Pharmacology, Incyte

6:30 End of Day


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