Use of Structure-Based Drug Design (SBDD) Approach in the Discovery of Potent and Selective Kinase Inhibitors

The presentation will outline the design and optimization of novel classes of potent and selective kinase inhibitors using a SBDD approach. Examples will be used to illustrate the use of structural information derived from homology models. These models were built based on crystal structures of closely related kinases. Dramatic improvements in potency and selectivity from HTS hits were achieved. Deep understanding of key interactions within the ATP binding site drove potency improvements. In addition, subtle differences with closely related kinases were exploited to achieve good selectivity against family members that have almost identical binding sites.