Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors

  • J Med Chem. 2014 Feb 13;57(3):1033-45. doi: 10.1021/jm401768t.
Steven T Staben  1 ,  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
Affiliations
  • 1. 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.
PMID: 24432870 DOI: 10.1021/jm401768t
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.