WEDNESDAY, JUNE 25
8:15am Continental Breakfast-with-the-Experts: Breakout Roundtable Discussions
Table 1: Doriano Fabbro Ph.D., Head of Kinase Biology & Technologies, Expertise Platform Kinases, Novartis Institutes of BioMedical Research
Multi-Targeted vs Selective Kinase Inhibitors: “To be Safe or Not to be Safe”
- multitargeted vs selective kinase inhibitors
- kinase inhibitors in non-life threatening diseases: how to solve the issues of safety
- how to target kinases outside of the ATP binding cleft
Table 2: Doris Hafenbradl, Ph.D., Executive Vice President, Screening & Proteins, Proteros Biostructures
Drug-Kinase Binding Kinetics
Table 3: Rob Bradbury, Ph.D., Principal Scientist, Cancer and Infection Research, AstraZeneca
Screening Compound Collections for Kinase Inhibitors - Focused, Subset or HTS?
- Merits of different approaches
- Profiling in-house and external tool compounds and clinical candidates
- IP considerations
Table 4: John Doukas, Ph.D., Senior Director, Pharmacology, TargeGen, Inc.
Maximizing the Therapeutic Index
- Can adjusting dosing routes, regiments, etc. maintain efficacy while minimizing toxicity?
- Can in vitro studies illuminate potential TI issues?
- Is it a target or small molecule issue, and what are the options for dealing with either case?
Table 5: Potential Roles for Companion Diagnostics in Clinical Development and Use of Therapeutic Protein Kinase Inhibitors
Stephen K. Burley, Ph.D., D. phil., F.R.S.C., Chief Scientific Officer and Senior Vice President, Research, SGX Pharmaceuticals, Inc.
- The Gleevec precedent in CML
- The “Tarceva versus Iressa” lesson
- Targets of opportunity
Expanding the Therapeutic Scope – Beyond Cancer
9:15am Roundtable Feedback by Moderators
9:45 Networking Coffee Break
10:15 Cell Cycle-Specific Regulation of Nucleotide Excision Repair in Human Cells
Elliot Drobetsky, Ph.D., Associate Professor, Faculty of Medicine, University of Montreal; Directeur, Axe de Recherche en Immunologie/Oncologie, Centre de Recherche, Hôpital Maisonneuve-Rosemont
Nucleotide excision repair (NER) is the only pathway available to humans for removing highly-genotoxic helix-distorting DNA lesions induced by a multitude of environmental carcinogens (eg., ultraviolet light) as well as by certain widely-employed chemotherapeutic drugs (eg., cisplatin). Recently my laboratory developed a sensitive, flow cytometry-based assay which has permitted, for the first time, the precise evaluation of NER efficiency as a function of cell cycle. The exploitation of this assay to reveal highly-novel mechanistic insights into the human NER process, and the attendant implications for cancer development and treatment, will be discussed.
10:45 Technology Watch Sponsored By .jpg "emd logo2")
WideScreen™ Assays for the Multiplex Detection and Quantitation of Cell Signaling Proteins and Serum Biomarkers
Scott Hayes, Ph.D., R&D Director. EMD Chemicals
Bead-based immunoassays allow multiplex analysis of 5-20 protein analytes from a single sample. This session will discuss select WideScreen™ Assays and their use in the characterization of cell signaling events and in the analysis of serum biomarkers. These assays include:
• Multiplex assays to analyze the expression and tyrosine phosphorylation status of several key receptor tyrosine kinases, enabling the profiling of protein kinase inhibitors in a cellular context.
• An assay that uses EpiTag™ Technology (Epitome Biosystems) for the simultaneous, multiplex quantitation of total and phosphorylated ERK pathway proteins in a single well.
• Highly validated and functionally defined serum biomarker panels developed in partnership with Rules Based Medicine.
11:15 Structure-Based p70 S6 Kinase Inhibitor Design
Faming Zhang, Ph.D., Associate Professor, Chemistry, Indiana University & Crown Bioscience
Ribosomal s6 kinase 1 has been indicated as a target for obesity and insulin resistance, it is also been linked to some tumor models. The crystal structure of the kinase domain complexed with some inhibitors will be reported.
11:45 Luncheon Workshop Sponsored By .gif "invitrogen logo2")
Accelerate Hit-to-Lead Programs with Invitrogen Discovery Services: Comprehensive Custom Assay Development Services including Screening and Profiling for Kinase Drug Discovery
Wendy R. Jory, Ph.D., Segment Leader, Discovery Services, Invitrogen Discovery Sciences
Invitrogen Discovery Sciences is a trusted partner for robust, validated custom assays and screening services. Choose from over 500 validated cellular or biochemical kinase assays for medium or high-throughput screening, or request a customized assay development program. This presentation will include a case study interrogating the JAK/STAT pathway with biochemical and cellular assays used for library screening and profiling respectively. Invitrogen services include any or all of the steps required to rapidly move from hit to lead including assay development, validation, scale up of enzymes and reagents, provision of cryopreserved cells, library screening, secondary screening and profiling with our SelectScreen™ Services. We also provide safety and liability testing services with P450 and hERG binding assays.
Structure-Based Design
Featured Presentation
1:15pm High-Throughput Crystallography of Protein Kinases as a Tool for Drug Discovery
Stefan Knapp, Ph.D., Principal Investigator, Phosphorylation Dependent Signalling Group, Structural Genomics Consortium, Oxford University, UK
Recently protein family targeted structural genomics has significantly increased the structural coverage of the human proteome. In the kinase area, our laboratory released more than 30 novel catalytic domain structures in addition to a large number of kinase inhibitor complexes during the past three years. These efforts lead to a significantly improved structural coverage of the human kinome. In addition, many representative structures for disease related kinases were determined where previously only structures of distantly related kinases were publicly available.
1:45 Crystal Structure of Plk-1 Solved Using a Selective DARPin
Roman Hillig, Ph.D., Scientist, Structural Biology/Lead Discovery, Bayer Schering Pharma AG
The kinase domain of Plk-1 turned out to be a challenging crystallization target. After all conventional crystallization screens had failed, we generated selective designed ankyrin repeat proteins (DARPins) and used them in co-crystallization screens. This approach finally yielded crystals which allowed structure determination and structure-based drug design.
2:15 Title to Be Announced
Michael Kothe, Ph.D., Senior Scientist, Pfizer Research Technology Center
2:45 Networking Refreshment Break
3:15 Speaker to be Announced
3:45 Targeting Multiple Conformations of Protein Kinases for the Design of Small-Molecule Inhibitors
Jeffrey Liao, Ph.D., TransTech Pharma, Inc.
Multiple conformations of a protein kinase target offer an opportunity to design small-molecule inhibitors with distinct but clinically useful profiles. In this talk, classification of the binding pockets in the kinase catalytic cleft in different conformational states will be provided. Targeting kinase multiple conformations as an emerging strategy in the field is exemplified with important small-molecule agents in the clinic. The structure-based analysis provides a rationale for thwarting the development of drug-resistant mutations in anti-kinase therapy.
4:15 Fragment Discovery and Characterization for a priori Selection of Mode of Action of Kinase Inhibitors
Gregg Siegal, Ph.D., CSO, ZoBio, The Netherlands
Fragment based drug discovery has significant advantages in generating novel, protectable compounds with good PK properties, yet traditionally requires large quantities of protein and is resource intensive, especially when applied to kinases. We have developed a technology called TINS (Target Immobilized NMR Screening) that makes highly efficient use of a single sample (few mg’s) of protein to rapidly screen our innovative fragment library. TINS has been used to selectively screen activated and non-activated kinases. Hits from TINS can be rapidly assayed for biologically activity, including ATP competition, using a proprietary solid phase technology. In this way structural studies can be carried out on a focus set of highly characterized fragments exhibiting the desired mode of action. Examples of our combination of hit discovery and characterization will be provided.
4:45 End of Conference