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

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

Affiliation

  • 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.

Figures