Monday, June 6
8:00 am Workshop Registration & Morning Coffee
9:00-12:00 pm Pre-Conference Short Course*
 Instructor: Kent Stewart, Ph.D., Research Fellow, Department of Structural Biology, Global Pharmaceutical Research and Development, Abbott
This instructional course has been designed for both chemists and biologists who are new to kinase research or have some experience in the field and would like to learn more. The Art and Science of Kinases course will cover topics that are critical to know for any kinase research program. This course will cover;
Protein structure; structural basis for “inactive” and “active” (DFG-out/in) forms; active site residues and electrostatics; gatekeeper; hinge, back-pocket.
Assays: different formats and readout; factors that control IC50 and Ki; ATP-concentration; off-rate; solubility; reasons for compound success and failure.
Inhibitors: approved drugs; inhibitor types; Type1/2; ATP-site directed; allosteric; covalent; hot-spots for ligand potency; common chemotypes.
Kinome selectivity: kinomics; visualizing and interpreting heat maps; conserved and variable active-site residues.
Technologies: high-throughput screening; fragment-based design; structure-based drug design.
Example case studies; late-stage challenges.
Instructor Biography: Dr. Kent Stewart has over 27 years experience in drug discovery, including contributions to over 15 kinase research programs at Abbott. Over 90 research publications in drug research with over 20 devoted to kinase research. Contributed to 8 candidate compounds, including 3 kinase candidates, with one in advanced clinical evaluation. Specialist in computer-aided drug design. Ph.D. in Organic Chemistry from University of California, Los Angeles, and post-doctoral work in biochemistry at the Rockefeller University.
* Separate Registration Required
|
12:00-1:30 Main Conference Registration
Main Conference
1:30 Chairperson’ s Remarks
Eli Wallace, Ph.D., Director, Medicinal Chemistry, Array BioPharma
1:40 Selective Small Molecule Kinase Inhibitors
Eli Wallace, Ph.D., Director, Medicinal Chemistry, Array BioPharma
Over the last decade, inhibition of various protein kinases has proven to be a successful therapeutic strategy to treat many diseases. While several multi-kinase inhibitors have demonstrated patient benefit, selective inhibitors are highly desirable from a safety and combination strategy prospective. Years ago, obtaining selective kinase inhibitors was a pipedream, as many researchers believed the conserved nature of the catalytic ATP binding pocket precluded design of truly selective small molecule inhibitors. However, these concerns have proven unfounded as many groups have designed and developed highly selective kinase inhibitors. This has been accomplished by both allosteric and ATP-competitive inhibitors. In this presentation, examples of selective allosteric and ATP-competitive kinase inhibitors of MEK, ErbB2, and others will be discussed.
2:10 Featured Speaker
14-3-3 Proteins Capture the Signaling Signatures of Hormones and Kinase Inhibitors
Carol MacKintosh, Ph.D., MRC Protein Phosphorylation Unit, College of Life Sciences, James Black Center, University of Dundee
We have devised a strategy to identify quantitative changes in the sets of proteins that are phosphorylated when PI 3-kinase/Akt, PKC/Erk/p90RSK and AMPK are activated in cells, and which are then captured by the 14-3-3 family of phosphoprotein-binding proteins. The differing response signatures of target proteins provide barcodes that report on how hormones and drugs affect these signaling pathways in cells and tissues.
2:40 Challenges and Opportunities with Kinase Inhibitor Selectivity
Peter Brandt, Ph.D., Principal Scientist, Beactica AB
In house assessment of kinase inhibitor promiscuity has previously been considered a challenge. However, a recent study of published kinase selectivity data suggests that inhibitor promiscuity can be assessed by selecting panels comprising a small set of non-redundant kinases. Thus, by determining the selectivity on a very limited but well chosen set of kinases, inhibitor promiscuity can be assessed in a very economical way. The methods used in this study and the conclusions drawn will be discussed in detail.
Sponsored By
3:10 Creation of Novel Genetically Engineered Cell Lines Showing Single-Kinase-Specific Sensitivity to Inhibition by FmkTrevor Collingwood, Ph.D., Manager Technology Research, Research Biotech, Sigma-Aldrich
Target validation is critical to drug discovery. We have used zinc finger nuclease technology to genetically engineer human cell lines so that all endogenous protein kinases are insensitive to the inhibitor molecule fmk yet retain normal function. On this background we then “dial in” additional genetic mutations in individual endogenous kinase genes to render them uniquely sensitive to inhibition by fmk. This novel approach enables functional validation of target kinases at physiological levels.
3:40 Networking Refreshment Break in the Exhibit Hall with Poster Viewing
4:20 The ABC's of Kinase Conformations
Henrik Möbitz, Ph.D., Investigator III, Global Discovery Chemistry, Novartis Institutes of BioMedical Research
Protein kinases are of medical interest because their disregulation is implicated in several diseases. We assemble and annotate the structural kinome from the Protein Data Bank on the basis of a universal residue nomenclature. Despite the inherent flexibility of kinases, a small set of clusters can be identified whose distribution shows a bias for the active conformation. A common rationale links the active and inactive state: stabilization of the active conformation, as well as inactivation by displacement of helix-C or the activation loop is governed by the interaction between helix-C and the DFG motif. In particular, the conformation of the DFG motif is tightly correlated with the propensity of helix-C displacement. Our analysis reveals detailed mechanisms for the displacement of helix-C and the DFG and improves our understanding of the role of individual residues. By pooling conformations from the whole structural kinome, the energetic contributions of sequence and extrinsic factors can be estimated in free energy analyses.
4:50 Targeting Alternative, Less Conserved Sites on Kinase Targets to Provide an Avenue for Greater Selectivity
Kenneth Comess, Ph.D., Senior Scientist III, Global Pharmaceutical Discovery, Abbott Laboratories
Unbiased, high throughput screening methods provide opportunities to identify novel, therapeutically relevant and selective small molecule ligands. Various techniques, including NMR, surface plasmon resonance and affinity selection-mass spectrometry, have been applied to serine/threonine and tyrosine kinase targets in our laboratories to seek alternative mechanisms of inhibition. Different screening formats are deployed at different stages in the early drug discovery process to take advantage of their relative efficiencies and the robustness of the information they provide. While the predominant classes of inhibitory ligands found in both biased activity-based and unbiased affinity-based screens are active site directed, the latter techniques have allowed identification of novel ligand binding sites and novel, selective compounds. One example will be described in detail, the discovery and characterization of non-ATP site inhibitors of the Jnk-1 and p38a MAP kinases.
5:20 Exploiting Activation-State Dependent Conformational Differences in Protein Kinases for Inhibitor Design and Optimization
Mark Ashwell, Ph.D., Vice President, Medicinal Chemistry, ArQule, Inc.
The presentation will describe the utilization of a new understanding of the role of hydrophobic residues within the ATP-binding cleft of inactive protein kinases in order to discover novel inhibitors. The inhibitory characteristics of these inhibitors in biophysical, biochemical and cell-based assays together with their binding mode characterization using X-ray crystallographic and mutational studies will be described.
5:50-7:00 Networking Cocktail Reception in the Exhibit Hall with Poster Viewing