Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

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• 作者：William McCoull ; Edward J. Hennessy ; Kevin Blades ; Claudio Chuaqui ; James E. Dowling ; Andrew D. Ferguson ; Frederick W. Goldberg ; Nicholas Howe ; Christopher R. Jones ; Paul D. Kemmitt ; Gillian Lamont ; Jeffrey G. Varnes ; Richard A. Ward ; Bin Yang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1118-1123
• 全文大小：351K
• ISSN：1948-5875

文摘

Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.