Fragment-based discovery of 7-azabenzimidazoles as potent, highly selective, and orally active CDK4/6 inhibitors

…, H Cheng, R Cheng, R Chopra, K Chung…

Index: Cho, Young Shin; Angove, Hayley; Brain, Christopher; Chen, Christine Hiu-Tung; Cheng, Hong; Cheng, Robert; Chopra, Rajiv; Chung, Kristy; Congreve, Miles; Dagostin, Claudio; Davis, Deborah J.; Feltell, Ruth; Giraldes, John; Hiscock, Steven D.; Kim, Sunkyu; Kovats, Steven; Lagu, Bharat; Lewry, Kim; Loo, Alice; Lu, Yipin; Luzzio, Michael; Maniara, Wiesia; McMenamin, Rachel; Mortenson, Paul N.; Benning, Rajdeep; O'Reilly, Marc; Rees, David C.; Shen, Junqing; Smith, Troy; Wang, Yaping; Williams, Glyn; Woolford, Alison J.-A.; Wrona, Wojciech; Xu, Mei; Yang, Fan; Howard, Steven ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 6 p. 445 - 449

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Citation Number: 15

Abstract

Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed> 1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in ...