| Literature DB >> 24432870 |
Steven T Staben1, 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.
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.Entities:
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Year: 2014 PMID： 24432870 DOI： 10.1021/jm401768t
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446