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

被引：38

作者：

Cho, Young Shin ^{[1
]}

Angove, Hayley ^{[2
]}

Brain, Christopher ^{[1
]}

Chen, Christine Hiu-Tung ^{[1
]}

Cheng, Hong ^{[1
]}

Cheng, Robert ^{[2
]}

Chopra, Rajiv ^{[1
]}

Chung, Kristy ^{[1
]}

Congreve, Miles ^{[2
]}

Dagostin, Claudio ^{[2
]}

Davis, Deborah J. ^{[2
]}

Felten, Ruth ^{[2
]}

Giraldes, John ^{[1
]}

Hiscock, Steven D. ^{[2
]}

Kim, Sunkyu ^{[1
]}

Kovats, Steven ^{[1
]}

Lagu, Bharat ^{[1
]}

Lewry, Kim ^{[2
]}

Loo, Alice ^{[1
]}

Lu, Yipin ^{[1
]}

Luzzio, Michael ^{[1
]}

Maniara, Wiesia ^{[1
]}

McMenamin, Rachel ^{[2
]}

Mortenson, Paul N. ^{[2
]}

Benning, Rajdeep ^{[2
]}

O'Reilly, Marc ^{[2
]}

Rees, David C. ^{[2
]}

Shen, Junqing ^{[1
]}

Smith, Troy ^{[1
]}

Wang, Yaping ^{[1
]}

Williams, Glyn ^{[2
]}

Woolford, Alison J. -A. ^{[2
]}

Wrona, Wojciech ^{[1
]}

Xu, Mei ^{[1
]}

Yang, Fan ^{[1
]}

Howard, Steven ^{[2
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Astex Pharmaceut Inc, Cambridge CB4 0QA, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 06期

关键词：

CDK4/6; pRb phosphorylation; mantle cell lymphoma; fragment-based screening; structure-guided optimization; MANTLE CELL LYMPHOMA; RETINOBLASTOMA PROTEIN; GENETIC ALGORITHM; CANCER; CYCLE; INACTIVATION;

D O I：

10.1021/ml200241a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：445 / 449

页数：5

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