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

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• 作者：Young Shin Cho ; Hayley Angove ; Christopher Brain ; Christine Hiu-Tung Chen ; Hong Cheng ; Robert Cheng ; Rajiv Chopra ; Kristy Chung ; Miles Congreve ; Claudio Dagostin ; Deborah J. Davis ; Ruth Feltell ; John Giraldes ; Steven D. Hiscock ; Sunkyu Kim ; Steven Kovats ; Bharat Lagu ; Kim Lewry ; Alice Loo ; Yipin Lu ; Michael Luzzio ; Wiesia Maniara ; Rachel McMenamin ; Paul N. Mortenson ; Rajdeep Benning ; Marc O'Reilly ; David C. Rees ; Junqing Shen ; Troy Smith ; Yaping Wang ; Glyn Williams ; Alison J.-A. Woolford ; Wojciech Wrona ; Mei Xu ; Fan Yang ; Steven Howard
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：3
• 期：6
• 页码：445-449
• 全文大小：404K
• 年卷期：v.3,no.6(June 14, 2012)
• ISSN：1948-5875

文摘

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.

Keywords:

CDK4/6; pRb phosphorylation; mantle cell lymphoma; fragment-based screening; structure-guided optimization