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Structure-Based Drug Design
June 4-5, 2009

Promega (larger)




Bio-IT World




Science AAAS

The Scientist

Monday, June 1

7:30 - 8:30 am Registration and Morning Coffee

8:30 Chairperson’s Remarks

New Kinase Targets and Novel Therapeutic Applications

8:35 Using Dose Responses to Identify Multiple Activities of Kinase Inhibitors

Petra Ross-McDonald, Ph.D., Senior Research Investigator, Bristol-Myers Squibb Co.

Multi-target pharmacology is recognized and investigated more aggressively for kinase inhibitors than for most other pharmaceutical targets. I will present two aspects of characterizing multi-target biology. The first is a successful mechanism of action study that analyzed a LIMK inhibitor series with an unknown secondary target: our unexpected findings shake common assumptions about the off-target effects of kinase inhibitors. Dose responses were key to this investigation of multi-target biology, and IC50 values from bioassays are a central currency of drug discovery. For compounds that hit multiple targets with differing IC50s, separating the distinct responses is necessary to make realistic connections between targets and biology. In the second part of my talk, I'll present new methods that for the first time allow routine identification and analysis of dose responses in the transcriptome, allowing transcription profiling data to be realistically compared with other bioassays.

9:05 Bruton’s Tyrosine Kinase (Btk), a Key Target in Lymphoid Disorders

C. I. Edvard Smith, M.D., Ph.D., Professor, Molecular Genetics, Laboratory Medicine, Karolinska Institute

Bruton’s tyrosine kinase plays a key role in B lymphocyte biology, since mutations cause an essential absence of B lymphocytes resulting in a human disease (X-linked agammagloibulinemia). This means that drugs targeting this kinase could be important in many areas, such as B cell lymphomas, allergies and autoimmunity. We have studied this kinase using biochemical, structural and genetic approaches, including microarrays. Btk belongs to the second largest family of cytoplasmic tyrosine kinases showing both unique and common features with the other family members.

9:35 PKC-z Inhibitors

John I.Trujillo, Ph.D., Principal Research Scientist, Pfizer-St. Louis

10:05 Networking Coffee Break, Poster and Exhibit Viewing

10:45 Inhibition of the ALK5 Pathway: In Vivo Evidence for Therapeutic Potential in Pulmonary Arterial Hypertension

Matt Thomas, Ph.D., Research Investigator, Novartis Institutes for Biomedical Research

Chemical Space

11:15 Knowledgebase and in silico Approaches in Drug Discovery
for Kinase Inhibitors

Ismail Ijjaali, Ph.D., Application Scientist, Life Science, Aureus Pharma

The scope of the presentation is to exemplify the combination of knowledgebase and in silico approaches to efficiently assist kinase profiling driven discovery. Particularly, kinase-specific topics will be covered including:

  • Annotating kinase knowledgebases
  • Charting kinase chemical space
  • Compound or target-centric profiling
  • Identification of multi-targeted inhibitors
  • Assessing compound potency and selectivity

11:45pm Lunch on Your Own

1:40 Chairperson’s Remarks

Drug Resistance

1:45 Inhibiting EGFR Kinases

Michael J. Eck, M.D., Ph.D., Professor, Biological Chemistry and Molecular Pharmacology, Dana Farber Cancer Institute, Harvard University Medical School

2:15 KinaseSwitch: A Technology Platform for the Inducible Inhibition of Kinase Targets in vivo    Taconic
Holger Kissel, Ph.D., Associate Director, Global Business Development, TaconicArtemis GmbH 

2:30 Sponsorship Opportunity Available

2:45Crosstalk and Redundancy between Rreceptor Tyrosine Kinase Networks

John Haley, Ph.D., Senior Research Director, Translational Research, OSI Pharmaceuticals

Multiple resistance mechanisms have been described for EGF receptor tyrosine kinase inhibitors In carcinomas with an epithelial phenotype, EGFR inhibitor resistance can derive from over activation of IGF-1 receptor or HGF receptor (Met), or from secondary mutation of EGFR (T790M). Crosstalk has been observed with EGF, HGF and IGF1 receptors and these receptors can create network redundancies leading to targeted drug resistance. In addition in progressing tumor cells with a mesenchymal phenotype, derived from an epithelial-mesenchymal-like transition, showed a marked reduction in sensitivity to EGFR TKIs and in several instances gained sensitivity to PDGFR and/or FGFR1 inhibitors. From these efforts, tissue markers can be identified for the matching of drug combinations, targeting the aberrant receptor signaling networks associated with cell survival and cancer progression, with appropriate patients. Approaches to the identification of patient stratification markers and patient selection markers are described that are applicable to many disease settings. These have required combinations of proteomic, gene expression, and IHC measurements which overlap and complement, to enable predictive markers and drug combinations to be refined.

3:15 Networking Refreshment Break, Poster and Exhibit Viewing

4:00 Targeted protein silencing with covalent drugs: Validation on Btk and ErbB kinases

Juswinder Singh, Ph.D., Chief Scientific Officer, Avila Therapeutics, Inc. 

4:30 Breakout Session with Moderated
Topic Discussions

Topic 1: The Challenge of Picking Targets

Topic 2: Cell Assays – How to Choose?

Topic 3:  Moderator: John Haley, Ph.D., Senior Research Director, Translational Research, OSI Pharmaceuticals

Kinase target selection and validation

  • siRNA models for target selection
  • synthetic lethal screens
  • substrate selection for cellular PD assays
  • context specific signaling and stromal interactions

Topic 4: ADME Issues associated with Kinase Inhibitors

5:30 Happy Hour in the Exhibit Hall

6:30 End of Day One