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Structure-Based Drug Design
June 4-5, 2009

Promega (larger)




Bio-IT World




Science AAAS

The Scientist

Tuesday, June 2

7:15 am Morning Coffee or Breakfast Presentation (Sponsorship Opportunity Available)

8:30 Chairperson’s Keynote Introduction

Keynote Presentation

8:40 To be or not to be Selective? What the past 10 Years have Taught us about Developing Effective Kinase Inhibitors

Isabelle Dussault, Ph.D., Director of Research, Amgen

Kinases were recognized early on as attractive drug targets based on the critical role they play in cell growth regulation. The challenges associated with discovering and developing selective small molecule inhibitors for these targets were, however, daunting. There have been some successes and some failures, but basic and clinical research over the last 5-10 years has yielded a wealth of information that can now be used to design the next generation of kinase inhibitors. I will discuss the identification and development of small molecule kinase inhibitors for c-Met as an example of an attractive target that has been challenging to drug.

Assay Development

9:30 Generation of Tagless, Physiologically Activated MAPKs in vitro

Ralph Graeser, Ph.D., Group Leader, Drug Discovery, ProQinase GmbH

Kinases from the MAP kinase family are typical signal transduction kinases, mediating cellular responses from a variety of stimuli. In vivo, these kinases are activated by their specific upstream kinases. Classically, therefore, cascade kinase assays have been performed in vitro to measure kinase activities of individual members. However, this does not discriminate between individual kinase activities, and we have, therefore, developed strategies to physiologically activate kinases from MAP kinase pathways. The talk will present a variety of approaches designed to activate individual kinases, followed by tag cleavage and removal of the upstream kinase(s).

10:00 Networking Coffee Break, Poster and Exhibit Viewing

10:45 Evaluation of a Novel Antibody-Free ADP Detection Assay for Protein Kinases

Hu Li, Ph.D., Manager, Molecular Discovery Research, GlaxoSmithKline

There exist a plethora of platform technologies that can be used for measuring kinase activities. However, there is none that fits all criteria in terms of sensitivity, ATP tolerance, robustness, throughput, and cost-effectiveness. New assay technology that can be easily adapted for both high-throughput screening (HTS) and mode of action (MOA) studies is still in high demand. We recently evaluated an ADP-Glo assay from Promega. This is a homogenous, signal increase assay that measures ADP production from a kinase reaction by converting it to ATP and subsequently quantifies ATP using luciferease in the presence of luciferin. Since the un used ATP in the reaction is depleted prior to ADP-ATP conversion, this assay shows excellent sensitivity at a dynamic ATP concentration range from low uM to high mM. Evaluation data of this novel assay technology in meeting the needs for both HTS and MOA will be presented.

11:15 Sponsored by Promega 
Luminescent ADP Detection as an Alternative to Radioactivity-based Kinase Assays
Jasbinder S. Sanghera, Ph.D., President and Chief Scientific Officer, SignalChem Inc
Protein kinases are key components in the relay of message in cells and dysregulation of these proteins leads to many disease states. SignalChem has been using the "Gold Standard" radiometric assay format for assaying the protein kinase targets during functional evaluation and compound screening processes. Recently, another assay technology has emerged based on luminescent ADP quantification that can be utilized for assaying protein kinase targets. Analysis of data generated with multiple protein kinase targets and the luminescent ADP quantification assay shows comparable results to the radiometric assay format. Therefore, the luminescent ADP quantification assay is an exciting new technology for evaluating catalytic function of protein kinases as well as other protein ATPases.  


11:45 Molecular Basis of the Plk1 Polo-box Domain Specificity and Development of a Highly Sensitive Plk1 ELISA Assay

Kyung S. Lee, Ph.D., Senior Investigator, Laboratory of Metabolism National Cancer Institute, National Institutes
of Health

Polo-like kinase 1 (Plk1) plays a critical role in the regulation of cellular proliferation. Deregulation of Plk1 activity is thought to promote tumorigenesis in humans. The polo-box domain (PBD) present in the C-terminal non-catalytic region of Plk1 forms a phosphoepitope-binding module and interacts with a phosphorylated target with a high affinity and specificity. Using a unique nature of Plk1-dependent phosphorylation on a kinetochore protein, PBIP1, and subsequent binding, we developed a rapid, highly sensitive, and specific Plk1 assay that can quantify the levels of Plk1 amount and activity with a small amount of total cellular proteins. This method may provide an innovative tool for accurate assessment of Plk1 activity in a wide range of cells and tissues.

12:15pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:40 Chairperson’s Remarks

Multi-Targeted Kinases

1:45 Discovery of Novel Inhibitors Targeting the T315I and Other Mutants of Abl Kinase

Xiaotian Zhu, Ph.D., Director, Ariad Pharmaceuticals Inc.

Despite tremendous clinical success of imatinib, mutation in the kinase domain of Bcr-Abl has become a major mechanism of acquired drug resistance. In order to overcome various mutations including the T315I gate-keeper residue mutation, we have designed and synthesized a series of chemical compounds which bind to Abl in the DFG in and out binding modes. Active compounds against both wild type and the T315I mutant Abl were identified. Further optimization has led to AP24534, an oral, multi-targeted kinase inhibitor, which is currently being investigated in Phase 1 clinical trial in patients with drug-resistant and refractory hematological malignancies, including chronic myeloid leukemia (CML).

2:15 The Use of Isogenic Cell Lines for Developing Targeted Therapies against Mutant PIK3CA

Ben Ho Park, M.D., Ph.D., Associate Professor of Oncology, Assistant Director, Medical Oncology Fellowship Training Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

My talk will be focused on how we use somatic cell gene targeting to “knock in” mutant PIK3CA into non-tumorgenic human breast epithelial cells, and then use these isogenic paired cell lines to 1) dissect out the effects of oncogenic PIK3CA mutations and 2) exploit these cell lines to identify drugs that specifically target cells with mutant PIK3CA, but are non-toxic to isogenic parental cells with wild type PIK3CA. Specific examples will be discussed, including plans for a clinical trial based upon this work.

2:45 Selected Oral Poster Presentations:

Dr. Sergei Timofeevski, Pfizer

Dr. George Lountos, NCI

3:15 Networking Refreshment Break, Last Chance for Poster and Exhibit Viewing

Screening and Lead Optimization

4:00 Fragment-based Discovery of Potent and Efficacious PKB Inhibitors

Marcel Verdonk, Ph.D., Director, Computational Chemistry and Informatics, Astex Therapeutics, Ltd.

Protein kinase B (PKB or Akt) is a serine/threonine kinase that plays a central role in the regulation of a variety of signal transduction pathways integral to the control of cell growth, differentiation and division. Inhibition of PKB is considered to be a potentially valuable approach to the treatment of cancers. We have applied fragment-based discovery – using X-ray screening (amongst other techniques) – to identify fragment hits against PKB. These hits were then evolved into potent and efficacious leads. We used structure-based design to identify compounds with certain selectivity profiles vs. other kinase targets. We will also show examples of nM PKB inhibitors that do not interact with the hinge region of the kinase. Finally, we demonstrate how the large number of protein-ligand structures obtained, in combination with the potencies of the compounds, can be used to automatically derive the individual group contributions to the potency.


4:30 Selected Oral Poster Presentation:

Dr. Jutta Fritz, Kinaxo

5:00 Rip2, a Kinase Involved in Autoimmunity: Building the Tools for Lead Identification

David Borhani, Ph.D., D. E. Shaw Research, LLC

Rip2 is a widely expressed Ser/Thr protein kinase that functions in apoptotic and extracellular signaling pathways. Rip2-deficient mice, although outwardly normal, exhibit innate and adaptive immune defects. Thus, Rip2 is a drug target for diverse autoimmune diseases, including rheumatoid arthritis, psoriasis, and Crohn’s disease. Here we describe the initial stages of a Rip2 lead identification program, spanning target production, assay development, high-throughput screening, and structure determination.

5:30 Panel Discussion: The Chemical Space – How Crowded is it?

6:15 End of Day Two