Cho, Young, Brain, Christopher, Chen, Christine, Cheng, Hong, Chopra, Rajiv, Giraldes, John, Kovats, Steven, Lagu, Bharat, Luzzio, Michael, Shen, Junqing, Yang, Fan, Wrona, Wojciech, O'Reilly, Marc, Howard, Steven, Loo, Alice, Haas, Kristy, Kim, Sunkyu, Lu, Yipin, Maniara, Wieslawa, Smith, Troy, Xu, Mei, Angove, Hayley, Cheng, Robert, Congreve, Miles, Dagostin, Claudio, J.Davis, Deborah, Feltell, Ruth, D.Hiscock, Steven, Lewry, Kim, McMenamin, Rachel, N.Mortenson, Paul, Benning, Rajdeep, C.Rees, David, Williams, Glyn and Woolford, Alison (2012) Fragment-Based Discovery and Structure-Guided Optimization of 2-Benzoyl-7-azabenzimidazoles as Potent, Highly Selective and Orally Active CDK4/6 Inhibitors. ACS Medicinal Chemistry Letters, 3 (6). pp. 445-449. ISSN 1948-5875

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 10 which showed >1000-fold selectivity for CDK4/6 over CDKs 1 and 2 in an enzymatic assay. Furthermore, compound 10 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

Item Type:	Article
Keywords:	CDK4/6, pRb phosphorylation, mantle cell lymphoma, fragment-based screening, structure-guided optimization
Date Deposited:	13 Oct 2015 13:15
Last Modified:	13 Oct 2015 13:15
URI:	https://oak.novartis.com/id/eprint/5875