Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors
Stuart C Wilson1, Butrus Atrash, Clare Barlow
1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK.
Abstract:
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 IC(50)=30 nM, CDK7-cyclin H with IC(50)=1.3 microM, and CDK9-cyclinT with IC(50)=0.11 microM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 microM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts.
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