Dataset Information

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

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.

SUBMITTER: Cho YS

PROVIDER: S-EPMC4025827 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Cho Young Shin YS Angove Hayley H Brain Christopher C Chen Christine Hiu-Tung CH Cheng Hong H Cheng Robert R Chopra Rajiv R Chung Kristy K Congreve Miles M Dagostin Claudio C Davis Deborah J DJ Feltell Ruth R Giraldes John J Hiscock Steven D SD Kim Sunkyu S Kovats Steven S Lagu Bharat B Lewry Kim K Loo Alice A Lu Yipin Y Luzzio Michael M Maniara Wiesia W McMenamin Rachel R Mortenson Paul N PN Benning Rajdeep R O'Reilly Marc M Rees David C DC Shen Junqing J Smith Troy T Wang Yaping Y Williams Glyn G Woolford Alison J-A AJ Wrona Wojciech W Xu Mei M Yang Fan F Howard Steven S

ACS medicinal chemistry letters 20120517 6

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. ...[more]

PMID: 24900493

Dataset Information

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

Publications

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

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