1254163-62-6Relevant articles and documents
Fragment-based discovery of 7-azabenzimidazoles as potent, highly selective, and orally active CDK4/6 inhibitors
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
supporting information; experimental part, p. 445 - 449 (2012/09/25)
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 a Jeko-1 mouse xenograft model.
