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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alkynes / chemical synthesis*
-
Alkynes / chemistry
-
Alkynes / pharmacology
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Benzimidazoles / chemical synthesis*
-
Benzimidazoles / chemistry
-
Benzimidazoles / pharmacology
-
Binding Sites
-
Cell Line, Tumor
-
Cell Movement / drug effects
-
Cell Survival / drug effects
-
Drug Screening Assays, Antitumor
-
Female
-
Humans
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology
-
Structure-Activity Relationship
-
Triple Negative Breast Neoplasms
-
p21-Activated Kinases / antagonists & inhibitors*
-
p21-Activated Kinases / chemistry
Substances
-
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
Associated data
-
PDB/4O0R
-
PDB/4O0T
-
PDB/4O0V
-
PDB/4O0X
-
PDB/4O0Y