Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors

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• 作者：Steven T. Staben ; Jianwen A. Feng ; Karen Lyle ; Marcia Belvin ; Jason Boggs ; Jason D. Burch ; Ching-ching Chua ; Haifeng Cui ; Antonio G. DiPasquale ; Lori S. Friedman ; Christopher Heise ; Hartmut Koeppen ; Adrian Kotey ; Robert Mintzer ; Angela Oh ; David Allen Roberts ; Lionel Rouge ; Joachim Rudolph ; Christine Tam ; Weiru Wang ; Yisong Xiao ; Amy Young ; Yamin Zhang ; Klaus P. Hoeflich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：1033-1045
• 全文大小：911K
• ISSN：1520-4804

文摘

Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.