9:10 Ex vivo Profiling of PI3K Inhibitors: A Translational Approach?
Gitte Neubauer, Ph.D., Vice President, Research Operations, Cellzome
We have developed novel and selective inhibitors for PI3Kgamma through the use of a proteomics assay for both screening and selectivity profiling. With this assay, we can monitor quantitatively the interaction of compounds with their kinase targets and off-targets directly from cultured cells or even tissue samples from patients. Using this method, we profiled our PI3K inhibitor leads in a translational medicine approach in primary leukocytes, which identifies off-targets as well as the effect of the compound on the physiological target.

9:40 An Old Story with New Impact - Selective Inhibition of Distinct CDKs from a Family of 13 Members
Bert Klebl, Ph.D., Senior Director, Discovery, GPC Biotech
Despite cyclin-dependent kinases (CDKs) being well known targets to the pharmaceutical industry, the great efforts to generate CDK inhibitor-based drugs largely failed so far. Here, we present a highly selective CDK9 inhibitor, which is active in cellular models for HIV replication and inflammation. Surprisingly, it is active and well tolerated in vivo, showing no overt toxicities. This lead is a novel and promising drug candidate and a useful chemical tool to better understand the molecular, phenotypical and pharmacological consequences of CDK9 inhibition. The selectivity profile of each CDK inhibitor from a templated lead optimization library is most critical in determining either toxicity or its potential therapeutic use and a chemogenomics strategy has been established to identify non-toxic CDK inhibitors, which are useful to combat cancer.

10:40 Structural Insights Into Bcr-Abl Kinase Domain Mutations and Drug Resistance: AP24534, A Potent Orally Active Inhibitor of T315I
William Shakespeare, Ph.D., Senior Director, Chemistry, ARIAD Pharmaceuticals Inc.

11:10 Kinase Inhibitors and the Issue of Cardiac Toxicity
Thomas L. Force, M.D., Department of Cardiology, Jefferson University

11:40 Curbing the Cardiotoxicity of Kinase Inhibitors: The Methyl that Save the Heart
Ariel Fernandez, Ph.D., Karl F. Hasselmann Chair in Engineering and Professor, Bioengineering, Rice University
Cardiotoxicity has become a major issue in the development of tyrosine kinase inhibitors. Thus, molecular cancer therapy would probably require novel and more stringent selectivity filters. The so-called "wrapping technology" has provided a promising approach to selective drug design since it targets structural features, which are not conserved across paralog proteins. We shall review its applicability in guiding a Gleevec redesign geared at curbing the cardiotoxicity of the parental compound.

12:10 pm Topically Applied Kinase Inhibitors for the Treatment of
Ocular Diseases
John Doukas, Ph.D., Senior Director, Pharmacology, TargeGen, Inc.
TargeGen has a strong preclinical program assessing the use of small molecule kinase inhibitors for the treatment of ocular diseases (such as age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and uveitis). These diseases share overlapping patholo gies (angiogenesis, edema, and/or infl ammation), addressable by targeting growth factor receptor tyrosine kinases (VEGFR, FGFR, PDGFR) and/or intracellular signaling cascades (Src family kinases, JAK kinases).  Aunique aspect of our pipeline is the ability to dose via a topical route, reducing systemic exposure and thus improving therapeutic indices. We have completed a Phase I trial in AMD and plan Phase
II trials for 2007, as well as future INDs.

12:40 Luncheon Workshop (Sponsorship Available) or Lunch on Your Own

1:10 Session Break2:20 Chairperson’s Remarks
David Hangauer, Ph.D., Senior Vice President, Research & Development,
Kinex Pharmaceuticals, LLC

3:40 Technology Watch (Sponsorship Available)

4:30 Maintaining Mechanistic Fidelity of Kinase Inhibitors from Lead Identification to the Clinic
Robert S. McDowell, Ph.D., Vice President, Research, Sunesis Pharmaceuticals Inc.
An approach to the discovery and early development of specific and potent inhibitors of protein kinases for the treatment of human cancers. In his talk, Dr. McDowell will discuss Sunesis’ approach to the identification, lead optimization and pharmacology-driven development of two kinase inhibitors now in clinical development.

10:40 The MK2/MK3 Pathway in Inflammation and Beyond
Jean-Baptiste Telliez, Ph.D., Principal Research Scientist, Inflammation Department, Wyeth Research
The role of MK2 as a downstream target of p38 MAPK and its essential role in pro-inflammatory cytokines production make it an attractive target for the development of an anti-inflammatory drug. We have recently investigated the potential role of MK3 in inflammation and how it relates to MK2 by generating MK3 knockout and MK2/3 double knockout mice. Furthermore, recent discovery of a role of MK2 as a checkpoint kinase and its important role in DNA damage response in p53-defective tumor make it also an attractive target for oncology.

11:10 Syk Inhibitor Program for Inflammatory Diseases
Esteban Masuda, Ph.D., Executive Director, Immunology, Rigel Pharmaceuticals Inc.

11:40 Multitargeted Receptor Tyrosine Kinase Inhibitor ABT-869--Discovery and Clinical Development
Yujia Dai, Ph.D., Research Investigator, Cancer Research, Abbott Laboratories
Tumor angiogenesis is primarily mediated by vascular endothelial growth factor receptor (VEGFR) and plated-derived growth factor receptor (PDGFR) tyrosine kinases. Inhibition of VEGFRs and PDGFRs has become a compelling approach for developing targeted cancer therapies. ABT-869 is a potent VEGFR/PDGFR multitargeted kinase inhibitor and currently in clinical development. This presentation will describe the discovery of ABT-869 and the preliminary results from phase I clinical trials.