ACS Medicinal Chemistry Letters · 2015 · 109 citations · 22 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryLead OptimizationAllosteric Drug DesignFragment-based OptimizationLigand BindingLigand-based DesignPotency OptimizationAllosteric Drug DiscoveryAllosteric Enzyme SitesAllosteric Kinase InhibitorsAllosteric Site IdentificationAllosteric Site TargetingFragment-based Allosteric DiscoveryKinase InhibitorsStructure-based Allosteric Drug Design
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.
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