Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Karpov AS

PROVIDER: S-EPMC4499825 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Karpov Alexei S AS Amiri Payman P Bellamacina Cornelia C Bellance Marie-Helene MH Breitenstein Werner W Daniel Dylan D Denay Regis R Fabbro Doriano D Fernandez Cesar C Galuba Inga I Guerro-Lagasse Stephanie S Gutmann Sascha S Hinh Linda L Jahnke Wolfgang W Klopp Julia J Lai Albert A Lindvall Mika K MK Ma Sylvia S Möbitz Henrik H Pecchi Sabina S Rummel Gabriele G Shoemaker Kevin K Trappe Joerg J Voliva Charles C Cowan-Jacob Sandra W SW Marzinzik Andreas L AL

ACS medicinal chemistry letters 20150522 7

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 in ...[more]

PMID: 26191365

Dataset Information

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

Publications

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

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