Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity†,10.1039/C4MD00280F

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Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity†

William McCoull,Edward J. Hennessy,Kevin Blades,Matthew R. Box,Claudio Chuaqui,James E. Dowling,Christopher D. Davies,Andrew D. Ferguson,Frederick W. Goldberg,Nicholas J. Howe,Paul D. Kemmitt,Gillian M. Lamont,Katrina Madden,Claire McWhirter,Jeffrey G. Varnes,Richard A. Ward,Jason D. Williams,Bin Yang

MedChemComm Pub Date : 08/19/2014 00:00:00 , DOI:10.1039/C4MD00280F

Abstract

A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise PAK1 potency and selectivity against targeted kinases. A liganded PAK1 crystal structure was utilised to guide compound design. Permeability and kinase selectivity impacted the translation of enzyme to cellular PAK1 potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good PAK1 cellular potency and has utility as a tool compound for target validation studies.