Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors.

Department of Chemistry, Nerviano Medical Sciences, Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. anna.vulpetti@nervianoms.com

N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50=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, IC50=20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.

PMID: 16260160 [PubMed - indexed for MEDLINE]