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

^†Department of Discovery Chemistry, ^‡Department of Translational Oncology, ^△Department of Pathology, ^§Department of Drug Metabolism and Pharmacokinetics, ^∥Department of Biochemical and Cellular Pharmacology, and ^⊥Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States

^# Medicinal Chemistry, Evotec, Abingdon, Oxfordshire OX144SA, United Kingdom

^∇ Pharmaron-Beijing, 6 Taihe Road, Beijing 100176, People’s Republic of China

^○ X-ray Crystallography Facility, University of California, Berkeley, California 94720, United States

^◆ Wuxi AppTec, 288 Fute Zhong Road, Shanghai 200131, People’s Republic of China

J. Med. Chem., 2014, 57 (3), pp 1033–1045

DOI: 10.1021/jm401768t

Publication Date (Web): January 16, 2014

*E-mail: stevents@gene.com. Phone: (650) 467-3103., *E-mail: hoeflich@gene.com. Phone: (650) 225- 6697.

Abstract

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.

Supporting Information

Full kinase selectivity data for compound 17, small-molecule X-ray data for compound 17, tabulated EC₅₀ data from the cell viability assays, and protein production/purification and X-ray crystallography conditions. This material is available free of charge via the Internet at http://pubs.acs.org

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Article

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

Abstract

Supporting Information

PDF

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

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