Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors

The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound αSβR-21 inhibits CDK2/cyclin E with IC50 = 30 nM, CDK7-cyclin H with IC50 = 1.3 μM, and CDK9-cyclinT with IC50 = 0.11 μM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI50 = 0.7 μM; and shows antitumour activity when dosed p.o. at 50 mg/kg to mice bearing HCT116 solid human tumour xenografts.