Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors |
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Authors: | Wilson Stuart C Atrash Butrus Barlow Clare Eccles Susan Fischer Peter M Hayes Angela Kelland Lloyd Jackson Wayne Jarman Michael Mirza Amin Moreno Javier Nutley Bernard P Raynaud Florence I Sheldrake Peter Walton Mike Westwood Robert Whittaker Steven Workman Paul McDonald Edward |
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Institution: | Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK. |
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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 μM, and CDK9-cyclinT with IC(50)=0.11 μM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 μM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts. |
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