Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.

摘要: The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels selectivity across the kinome. Herein we report our structure-based optimization strategy a dibenzodiazepine hit 1, discovered in fragment-based screen, yielding highly potent and selective PAK1 such as 2 3. Compound was cocrystallized with to confirm binding an site reveal key interactions. 3 modulated at cellular level due its enabled valuable research interrogate biological functions kinase.