Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors

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• 作者：James J. Crawford ; Wendy Lee ; Ignacio Aliagas ; Simon Mathieu ; Klaus P. Hoeflich ; Wei Zhou ; Weiru Wang ; Lionel Rouge ; Lesley Murray ; Hank La ; Ning Liu ; Peter W. Fan ; Jonathan Cheong ; Christopher E. Heise ; Sreemathy Ramaswamy ; Robert Mintzer ; Yanzhou Liu ; Qi Chao ; Joachim Rudolph
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：5121-5136
• 全文大小：709K
• ISSN：1520-4804

文摘

The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.