Optimization of a series of 3-alkynyl-1-heteroaryl-benzimidazoles toward potent and selective group-II PAK inhibitors will be described. Within these type I ½ class kinase inhibitors, filling hydrophobic space past the methionine gatekeeper as well as optimizing the biaryl torsion directing the hinge-binding element was important for both potency and selectivity. A structure-based hypothesis driven by back pocket residue identity and flexibility will be used to rationalize both PAK-group and kinome selectivity. Compound <b>2</b> proved a useful tool to evaluate group-II PAK biology in vitro.

Selective inhibition of group-II p-21-activated kinases (PAKs)

249th National Meeting (2015)

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