SUNDAY, JUNE 22
5pm - 6pm Early Registration
MONDAY, JUNE 23
7:30am Registration and Morning Coffee
Non-ATP Competitive Inhibitors
8:30 Chairperson’s Remarks
8:35 Gleevec and Follow up on Allosteric Inhibitors
Doriano Fabbro, Ph.D., Head of Kinase Biology & Technologies, Expertise Platform Kinases, Novartis Institutes of BioMedical Research
Imatinib resistance primarily occurs in the advanced stages of Ph+ CML and is mainly due to mutations in the tyrosine kinase domain of BcrAbl. Nilotinib and Dasatinib are potent second generation Bcr-Abl inhibitors that inhibit most of the imatinib resistant mutations in the advanced stages of Ph+ CML except for T315I. In order to circumvent issues related to targeting the ATP binding site of the T315I Bcr-Abl mutant, specific, non-ATP competitive inhibitor of cellular Bcr-Abl kinase activity were discovered that bind to the Abl-myristate binding site. The finding that significant inhibition of Bcr-Abl activity can be achieved using these non-competitive inhibitors that bind to the myristate binding site will be discussed.
9:05 The Promise and Perils of Working Outside of the ATP Box in Kinase Inhibitor Discovery
Jeffrey F. Ohren, Ph.D., Principal Scientist, Lead Discovery Technologies, Groton Laboratories, Pfizer Inc.
9:35 Protein Kinases Relevant for Neurodegenerative Diseases
Marcie Glicksman, Ph.D., Senior Director, Leads Discovery, Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women’s Hospital
The Laboratory for Drug Discovery in Neurodegenerative Diseases (LDDN) at the Harvard NeuroDiscovery Center is a model for how academia can apply its research findings to drug discovery. Our primary mission is to identify chemical agents from our library of 150,000 compounds that can serve as lead structures for the development of therapeutics for neurodegenerative diseases. Some case studies of protein kinase projects will be discussed.
10:05 Networking Coffee Break, Poster and Exhibit Viewing
| 10:45 Characterization of Kinase Inhibitors with Homogeneous, Competitive TR-FRET Binding Assays |
Sponsored by
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Connie Lebakken, Ph.D., Senior Scientist, Invitrogen
As kinase drug discovery progresses, it has become clear that an increasing number of promising therapeutics, whether by design or serendipity, bind preferentially to the inactive form of a kinase. Specifically, type II inhibitors bind to both the ATP-binding site in addition to a hydrophobic pocket exposed in the inactive, DFG-out kinase conformation. Examples of compounds with such a binding mode include Gleevec, Sorafenib, and BIRB-796. This mechanism of inhibition offers significant advantages over standard type I inhibitors, which bind solely to the ATP site, including the potential for greater selectivity. While kinase activity assays are facile & cost-effective, they by their very nature measure the signal from an active kinase, and are thus not well suited to characterize type II inhibitors. However, methods that measure direct binding of compounds, rather than catalysis, can be effectively applied to either active or inactive kinase preparations. In order to identify, characterize, and differentiate both type I and type II kinase inhibitors, we have developed a binding assay platform based on Alexa Fluor® 647 conjugated to kinase inhibitor scaffolds. Binding of an Alexa Fluor® conjugate or “tracer” to a kinase is detected by addition of a europium-labeled anti-tag antibody. Binding of the tracer & antibody to a kinase results in a high degree of FRET, whereas displacement of the tracer with a kinase inhibitor results in a loss of FRET. We demonstrate broad coverage for selected binding probes across the human kinome by TR-FRET, and inhibitor validation for selected targets. |
Cell Cycle Kinases
11:15 Targeting Cell Cycle Kinases for the Treatment of Cancer
Jurgen Moll, Ph.D., Director, Cell Biology, Nerviano Medical Sciences SRL
An overview on the stage of small molecule cell cycle kinase inhibitors for the treatment of cancer will be given. Case studies on the development of inhibitors for some of the most attractive targets such as inhibitors for Aurora kinases, PLK-1 and CDC-7 will be described.
11:45 Discovery of AZD7762 and a Novel Class of Thiophene Carboxamide Urea Checkpoint Kinase Inhibitors
James Janetka, Ph.D., Principle Scientist, AstraZeneca
A novel class of potent thiophene carboxamide (TCU) checkpoint kinase inhibitors was discovered via high-throughput screening. The checkpoint kinase inhibitors were optimized for potency, dmpk, and kinase selectivity against IKKβ and other cell cycle kinases. The dual Chk1/Chk2 TCU kinase inhibitor candidate drug AZD7762 is currently being evaluated in several Phase I clinical studies for cancer treatment.
12:15 pm Lunch on your own
Targeting Tumors
1:40 Chairperson’s Remarks
1:45 Influence of T790M Mutation in EGFR Kinase on Drug Resistance
Michael J. Eck, M.D., Ph.D., Professor of Biological Chemistry and Molecular Pharmacology, Dana Farber Cancer Institute, Harvard Medical School
2:15 Multitargeted Kinase Inhibitor Dasatinib and it’s Efficacy in Solid Tumors: from a Biomarker Perspective
Xi-De Wang, Ph.D., Investigator II, Bristol-Myers Squibb Co.
2:45 Technology Watch
Kinase-Glo® Assays Platform: A Robust Bioluminescent System for Monitoring the Activities of all Types of Kinases
Said A. Goueli, Ph.D., Research Fellow, Cell Analysis Group, Research and Development, Promega Corp.
The luminescence based Kinase-Glo assay platform has gained wide acceptance in many drug screening programs. The assay measures ATP depletion, a general feature of all kinases, as a read-out for kinase activity. Thus it is applicable to most kinase-substrate combinations with no prior substrate modification. Examples of its use with several protein kinases using peptides as well as protein substrates will be presented, as well as examples of its use with some non-protein kinases (lipid kinases, sphingosine kinases, ceramide kinases, and glucokinases). The assay can also be used with kinases that use pre-phosphorylated substrates such as GSK-3ß and CK1, or with kinases that phosphorylate on multiple sites on a substrate. Data showing the use of the assay with higher concentrations of ATP (up to 500µM) will also be presented. Utilizing higher ATP levels maximizes the probability of selecting non-ATP binding site inhibitors during screening. Data comparing Kinase-Glo to other luminescent and TR-FRET based assays will also be presented.
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3:15 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 The Discovery of the Aurora Kinase Inhibitor SNS-314
Johan D. Oslob, Ph.D., Senior Scientist, Sunesis Pharmaceuticals
SNS-314 is a potent and selective inhibitor of the Aurora kinases and is currently undergoing Phase 1 clinical studies. This presentation describes the discovery process that led to the selection of SNS-314 as a clinical candidate.
4:30 5-Substituted-4-Anilinoquinazolines: New erbB2 Inhibitors from an Old Template
Rob Bradbury, Ph.D., Principal Scientist, Cancer and Infection Research, AstraZeneca
This presentation will briefly review the discovery and evolution of anilinoquinazolines as ATP-competitive kinase inhibitors, before focusing on more recent medicinal chemistry of 5-substituted-4-anilinoquinazolines as potent and selective inhibitors of erbB2 receptor tyrosine kinase. The role of the quinazoline 5-substituent in binding to the kinase ribose pocket will be highlighted, optimisation of PK parameters and physical properties will be outlined, and activity of these inhibitors in pre-clinical models will be described.
5:00 Happy Hour in the Exhibit Hall
6:00 End of Day One