Literature DB >> 24900493

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.

Young Shin Cho1, Hayley Angove2, Christopher Brain1, Christine Hiu-Tung Chen1, Hong Cheng1, Robert Cheng2, Rajiv Chopra1, Kristy Chung1, Miles Congreve2, Claudio Dagostin2, Deborah J Davis2, Ruth Feltell2, John Giraldes1, Steven D Hiscock2, Sunkyu Kim1, Steven Kovats1, Bharat Lagu1, Kim Lewry2, Alice Loo1, Yipin Lu1, Michael Luzzio1, Wiesia Maniara1, Rachel McMenamin2, Paul N Mortenson2, Rajdeep Benning2, Marc O'Reilly2, David C Rees2, Junqing Shen1, Troy Smith1, Yaping Wang1, Glyn Williams2, Alison J-A Woolford2, Wojciech Wrona1, Mei Xu1, Fan Yang1, Steven Howard2.   

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 a Jeko-1 mouse xenograft model.

Entities:  

Keywords:  CDK4/6; fragment-based screening; mantle cell lymphoma; pRb phosphorylation; structure-guided optimization

Year:  2012        PMID： 24900493      PMCID： PMC4025827          DOI： 10.1021/ml200241a

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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