Structure-Based Drug Design to the Discovery of New 2-Aminothiazole Cdk2 Inhibitors.

Abstract N -(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1 ) was found active (IC 50  = 808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3-thiazol-2-yl)amino] benzenesulfonamide (compound 4 , IC 50  = 20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.