Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
Basic Information
ID: ALA2086364
Journal: ACS Med Chem Lett
Title: Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
Authors: Cho YS, Angove H, Brain C, Chen CH, Cheng H, Cheng R, Chopra R, Chung K, Congreve M, Dagostin C, Davis DJ, Feltell R, Giraldes J, Hiscock SD, Kim S, Kovats S, Lagu B, Lewry K, Loo A, Lu Y, Luzzio M, Maniara W, McMenamin R, Mortenson PN, Benning R, O'Reilly M, Rees DC, Shen J, Smith T, Wang Y, Williams G, Woolford AJ, Wrona W, Xu M, Yang F, Howard S.
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.
CiteXplore: 24900493
DOI: 10.1021/ml200241a
Patent ID: ┄