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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 3 Pg. 1033-45 (Feb 13 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24432870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-(1-(2-aminopyrimidin-4-yl)-2-((2-methoxyethyl)amino)-1H-1,3-benzodiazol-6-yl)ethynyl)cyclohexan-1-ol
• Alkynes
• Antineoplastic Agents
• Benzimidazoles
• Pyrimidines
• p21-Activated Kinases

Topics

• Alkynes (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Triple Negative Breast Neoplasms
• p21-Activated Kinases (antagonists & inhibitors, chemistry)