Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors
N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50=808nM) 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, IC50=20nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.
structure-based drug design cdk2 crystal structures cyclin-dependent kinase ligand docking ligandprotein interactions