Details

Autor(en) / Beteiligte

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

Titel

Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivityElectronic supplementary information (ESI) available: Synthetic details for the preparation of compounds, kinase selectivity data, and protein production/purification and X-ray crystallography conditions. See DOI: 10.1039/c4md00280f

Erscheinungsjahr

2014-09

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. SAR optimisation led to novel PAK1 inhibitors with good potency and kinase selectivity.