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Fragment-Based Discovery and Structure-Guided Optimization of 2-Benzoyl-7-azabenzimidazoles as Potent, Highly Selective and Orally Active CDK4/6 Inhibitors

Cho, Young and Brain, Christopher and Chen, Christine and Cheng, Hong and Chopra, Rajiv and Giraldes, John and Kovats, Steven and Lagu, Bharat and Luzzio, Michael and Shen, Junqing and Yang, Fan and Wrona, Wojciech and O'Reilly, Marc and Howard, Steven and Loo, Alice and Haas, Kristy and Kim, Sunkyu and Lu, Yipin and Maniara, Wieslawa and Smith, Troy and Xu, Mei and Angove, Hayley and Cheng, Robert and Congreve, Miles and Dagostin, Claudio and J.Davis, Deborah and Feltell, Ruth and D.Hiscock, Steven and Lewry, Kim and McMenamin, Rachel and N.Mortenson, Paul and Benning, Rajdeep and C.Rees, David and 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

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