Wednesday, June 25, 2008
1:15 - 5:00 pm PRE-CONFERENCE WORKSHOP*
Designing Kinase Inhibitors
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 Speaker to be Announced
2:45 Networking Refreshment Break
3:15 Utilizing Protein Conformational Flexibility in Drug Design: A Case Study in Kinases
Glenn Noronha, Ph.D., Director of Chemistry, TargeGen, Inc.
We describe the development of highly potent kinase inhibitors against SRC, VEGFr, ABL, and ABL-T315I. The inhibitors were designed by a structure-guided approach using target flexibility by building models of conformations of the proteins not seen in previous crystal structures. Series of compounds described here show single digit nanomolar inhibition, one of which is currently in clinical trials. The approach demonstrates the critical nature of introducing an interaction with a single highly-conserved glutamate on the C-helix that plays a pivotal role in kinase activation
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 Workshop
*Separate registration is required.