Day 2

Tuesday, June 7

7:30-8:15 Morning Coffee
(Breakfast Workshop Sponsorship Available)

8:25 Chairperson's Remarks
Dr. Martin McMahon, Efim Guzik Distinguished Professor of Cancer Biology, Cancer Research Institute, UCSF Comprehensive Cancer Center

Kinase Profiling

8:30 The Importance of Large Scale Profiling in Discovery and Development of Multi-Target Protein Kinase Inhibitors
Dr. Dieter Marmé, Chairman, ProQinase GmbH
Protein kinases are promising therapeutic targets in many diseases. In oncology it becomes evident that protein kinase inhibitors of the new generation will preferably inhibit more than one of those kinases involved in the various mechanisms of tumor progression. This requires new strategies in discovery and development of such compounds. Hit discovery will be based on an appropriate panel of kinases and lead development will need large scale profiling on as many kinases as possible. ProQinase's technology platform has been developed to serve those needs.

9:00 Characterization of the Mechanism of Action of a Novel Class of CDK Inhibitors Using Multiple Three-Hybrid Based Target Fingerprinting Approaches
Dr. Nikolai Kley, VP, Head of Research, GPC Biotech Inc.
The human proteome includes more than 500 kinases, as well as many other purine-binding proteins. Many kinase inhibitors act in an ATP-competitive manner and, consequently, have the potential of interacting to a variable extent with multiple members of these protein families, as well as other types of proteins. Scanty knowledge of the target spectrum of small molecule kinase inhibitors can pose a challenge in evaluating their mechanisms of action and potential applications. Here we describe chemical proteomics approaches that are based on the use of chemical dimerizers and enable the identification and characterization of the cellular target spectrum of kinase inhibitors, and their application towards the characterization of a novel class of potent, proteome-wide selective inhibitors of cyclin dependent kinases (CDKs). The target spectra and activity profiles suggest that this class of compounds may be further exploited as a novel source of selective kinase inhibitors with application to the study or treatment of proliferative diseases such as cancer, as well as potentially other diseases, including neuro-degeneration, cardiac hypertrophic growth and AIDS.

10:00 Coffee Break, Poster and Exhibit Viewing

10:45 Immunoaffinity Profiling of Tyrosine Phosphorylation in Cancer Cells
Dr. Christopher Bunker, Director, Business Development, Cell Signaling Technology
The presentation will describe the application on a breakthrough phosphoproteomics technology to the identification of novel phosphorylation site biomarkers of kinase target activation and kinase inhibitor efficacy. We have developed and applied a method of phosphopeptide affinity purification and tandem mass spec that has enabled the discovery of phospho-signatures of activated kinases in cancer models, xenografts and primary human tissues. We have identified nearly 4,000 phosphorylation sites and we are validating newly discovered biomarkers of kinase activation in cancer.

11:15 Selective Small Molecule Series with Multi-Kinase Activity 
Dr. Scott Galasinski, Senior Scientist, Team Leader, Enzymology and Lead Follow-up, Amphora Discovery Corporation
The potential for targeting kinases in the treatment of cancer holds the promise of creating molecular based therapies with low toxicity. Current anti-kinase drugs often show activity against more than one target, indicating that inhibition of multiple pathways or at multiple points within a pathway is beneficial or necessary. Accurate profiling of small molecules against a large panel of enzymes allows for the rapid identification of chemical series with selectivity towards several distinct kinases without being promiscuous.

11:45 Lunch on your own (sponsorship available)

1:10 Chairperson's Remarks

Drug Targets - Case Studies

1:15 Identification and Functional Validation of a Novel Kinase, IKK-i/K151, in Inflammation
Dr. Sabita Sankar, Group Leader, Experimental Therapeutics, Celgene Corporation
We have taken a functional genomics approach to identify novel kinases induced in inflammatory paradigms. IKK-i/K151 was identified as a TNF-a inducible kinase in endothelial cells. Our data using engineered cell lines suggest that expression of IKK-i activates transcription factors such as IRF3 and NFkB. This results in the coordinate expression of various cytokines and chemokines. In particular, the expression of interferon a/b results in the autocrine and paracrine triggering of the JAK-STAT pathway thereby causing up-regulation of genes involved in the type I interferon response. We describe the utility of the engineered cell line to screen for inhibitors of IKK-i and the identification of prototype inhibitors of IKK-i with activity in vitro and in vivo. The potential therapeutic applications for such inhibitors will be discussed. 

1:45 BRAF as Therapeutic Target in Human Cancer
Dr. Martin McMahon, Efim Guzik Distinguished Professor of Cancer Biology, Cancer Research Institute, UCSF Comprehensive Cancer Center
The RAS-regulated RAF-MEK-ERK pathway is activated in a large percentage of human malignancies and consequently, is a major target for new drug discovery. Using systems for the conditional activation of RAF protein kinases in mammalian cells we are exploring the contribution of this pathway to the aberrant proliferation of the cancer cell. Such explorations will allow us to define the utility of agents that target this pathway and may also suggest avenues by which signal pathway inhibitors may be used in conjunction with conventional chemotherapeutic agents.

2:15 Coffee Break, Poster and Exhibit Viewing

3:00 Discovery of BAY 43-9006, a Dual-Acting raf and VEGFR-2 Inhibitor for theTreatment of Cancer
Dr. Jacques Dumas, Associate Director, Medicinal Chemistry, Bayer Healthcare
The diaryl urea BAY 43-9006 was discovered as part of a collaboration between Bayer and Onyx Pharmaceuticals. This compound is a potent inhibitor of raf and VEGFR-2 kinases currently in Phase III clinical trials. The present talk will focus on the lead generation effort that led to the discovery of BAY 43-9006, and will provide a summary of recent in vitro and in vivo studies demonstrating its dual mechanism of action.

3:30 A Novel Approach to the Design of Kinase Inhibitors: A Directed Exploration of Synthesis Strategies Using Both Target-Based and Ligand-Based Models
Dr. Stephan Schurer, Senior Director, Content Development, Eidogen-Sertanty, Inc.
In this case study we compare different approaches for the suggestion of novel, synthetically accessible small-molecule kinase inhibitors. We explore synthetically accessible chemical space utilizing known ligands bound to common targets (ligand crossover) and pharmacophoric-based protein structure-independent eScreen models derived from known structure-activity relationship (SAR) data. Our approach arrives at likely inhibitors with consideration of synthetic accessibility and should allow for rapid optimization follow-up. We present the results of several simulations and the underlying computational methodologies.

4:00 P38 Inhibitors for the Treatment of Allergic and Autoimmune Diseases
Dr. Karim Dabbagh, Principal Research Scientist, Inflammatory, Autoimmune Diseases and Transplantation, Roche Pharmaceuticals
Cytokines such as TNF-alpha and IL-1beta play a critical role in the development of autoimmnune diseases such as rheumatoid arthritis and psoriasis and have been implicated in the pathogenesis of asthma. P38 inhibitors have been shown to inhibit the production of these cytokines. This talk will describe the pharmacological characterization of such p38 inhibitors in cell based assays as well as animal models of RA and asthma.

4:30 Panel Discussion: Lessons Learned in Kinase Drug Discovery

5:00 End of Conference

Call for Sponsors and Exhibitors
Showcase your company’s expertise, brand your solutions and develop revenue opportunities
with qualified decision-makers by becoming an Exhibitor or Sponsor of
Protein Kinase Targets. Contract exhibit booth space by February 28, 2005 and you
will save $200! If you want to discuss sponsoring or exhibiting at this conference,
please contact Suzanne Carroll at 781-972-5452 or scarroll@healthtech.com.