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ACS Med Chem Lett. 2015 May 22;6(7):776-81. doi: 10.1021/acsmedchemlett.5b00102. eCollection 2015 Jul 9.

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

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Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.


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


PAK1; allosteric inhibitor; dibenzodiazepine; p21 activated kinase; tool compound

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