The Cyclin-dependent kinases (CDKs) are members of the serine-threonine protein kinase family, and are known to possess cell-cycle related functions. Aberrant cell cycle control may arise from the mutation or inactivation of tumour suppressor genes coupled with the frequently observed over-expression of CDK2, which has been validated as an attractive target for cancer chemotherapy.Previous structure-activity relationship investigations have indicated 2-arylamino-6-alkoxypurines are potent ATP-competitive inhibitors of CDK2 activity. One of the most potent and kinase-selective compounds in this series, NU6102 (CDK2; IC50 = 5 nM), has been the subject of extensive studies to further improve selectivity by focusing on modification of the purine 6-position.A focussed series of 6-alkyl- and 6-arylpurines was synthesised by Suzuki cross-coupling in excellent yields. 6-Phenyl- and 6-(3-phenyl)phenyl-2-sulfanilylpurines were potent inhibitors of CDK2 (IC50 = 24 nM and 36 nM, respectively). Interestingly, the biphenyl compound exhibited excellent selectivity for CDK2 against a panel of kinases.

Development of 6-substituted purines as selective inhibitors of cyclin-dependent kinase 2 (CDK2)

239th National Meeting (2010)

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