Day 1 | Day 2 | Download Brochure | Delegate List
Thursday, April 29
7:30 am Breakfast Workshop Presentation (Sponsorship Opportunity Available) or Morning Coffee
8:15 Chairperson's Opening Remarks
8:20 Featured Presentation
Discovery of Novel Kinase Inhibitors Using Structure-Based Design
Jose Duca, Ph.D., Senior Principal Scientist, 3D-Drug Design Department, Merck Research Laboratories
9:00 Structures of Protein Kinase CK2 and their Consequences for Inhibitor Design
Karsten Niefind, Ph.D., Department of Chemistry, Institute of Biochemistry, University of Cologne
As a constitutively active enzyme apparently lacking inactive states protein kinase CK2 was addressed for a long time exclusively with typical type-I-inhibitors targetting the canonical ATP-site. Recent CK2 structures, however, revealed inactive conformations and allosteric small molecule binding sites: type-II- and type-III-inhibitors of CK2 with possibly enhanced selectivity are now realistic options.
9:30 Utilization of a Chemocentric Approach for the Rational Structure Based Design of DFG-out Allosteric B-Raf Inhibitors
Justin Dietrich, Ph.D., Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy
The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increased kinase activity in approximately 7% of all human cancers, establishing B-Raf as an important therapeutic target for inhibition. Through the use of an iterative program that utilized a chemocentric approach and a rational structure based design, we have developed novel, potent, and specific DFG-out allosteric inhibitors of B-Raf kinase. Modeling and docking studies suggest these inhibitors bind in an alternate DFG-out conformation of B-Raf V600E that is facilitated by the movement of Glu501.
10:00 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Structural Bioinformatics-Based Prediction of Selectivity of a p38 MAP Kinase Inhibitor
Li Xing, Ph.D., Senior Principal Scientist, Pfizer Global Research and Development, St. Louis Laboratories
11:15 Rational Mutagenesis to Support Structure-Based Drug Design: MAPKAP Kinase 2 as a Case Study
Maria Argiriadi, Ph.D., Prinzipal Scientist, Molecular Pharmacology, Abbott Laboratories
11:45 Localized Control of Kinase Pharmacology
John D. Scott, FRS, Edwin G. Krebs-Speights Professor of Cell Signaling and Cancer Biology, Howard Hughes Medical Institute; Department of Pharmacology, University of Washington School of Medicine
12:15 Walk and Talk Luncheon in the Exhibit Hall (Last Chance for Poster and Exhibit Viewing)
1:55 Chairperson's Remarks
2:00 Developing Small Molecule Inhibitors for JAK 1 and 2
Jordan Fridman, Ph.D., Director, Pharmacology, Incyte
2:30 Kinetic Analysis of the Enzyme Mechanism and the Allosteric Inhibition of CHK1
Jacques Ermolieff, Ph.D., Senior Principal Scientist, Biochemical Pharmacology, Pfizer, La Jolla
Similar to Akt and P38 MAP kinases, the discovery of a new allosteric site on CHK1 provides opportunity to design more potent inhibitors that do not compete with ATP and that display a better selectivity profile toward other kinases. During this presentation, we will provide further details regarding the characterization of this allosteric binding site in the presence of two inhibitors from novel chemical series (i.e. a carbamate and a semicarbazide series) using biochemical, biophysical and crystallography methodologies. In addition, we will briefly discuss the kinetic mechanism of CHK1 for the binding of the substrate peptide and ATP.
3:00 Networking Refreshment Break
3:20 Discovery of PF-04577806, a Potent and Selective PKCbeta Inhibitor
Hui Li, Ph.D., Senior Principle Scientist, Pfizer Global Research & Development
PKC is a family of phospholipids-dependent, serine/threonine kinases involved in intracellular signal transduction. Our screening efforts identified pyrrolopyrazole (PP series) as PKCb inhibitor. Through modification at both the head and tail regions of the template, single digit nanomolar potency was achieved in both biochemical and cellular assays. A balance between potency, permeability and in vitro metabolic stability of this series was accomplished through careful control of lipophilicity (logD), basicity (pKa) and the number of effective H-bonds. In the absence of X-ray crystallography information, good general kinase selectivity and PKC isozyme selectivity were also achieved through introduction of key stereogenic centers.
3:50 Docking Sites of MAPK
Lee Bardwell, Ph.D., Professor, Dept. of Developmental & Cell Biology, University of California, Irvine
4:20 Panel Discussions: Kinase Inhibitors – What is Next?
4:50 End of Conference
Day 1 | Day 2