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

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 fra...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2015-07, Vol.6 (7), p.776-781
Main Authors: Karpov, Alexei S, Amiri, Payman, Bellamacina, Cornelia, Bellance, Marie-Helene, Breitenstein, Werner, Daniel, Dylan, Denay, Regis, Fabbro, Doriano, Fernandez, Cesar, Galuba, Inga, Guerro-Lagasse, Stephanie, Gutmann, Sascha, Hinh, Linda, Jahnke, Wolfgang, Klopp, Julia, Lai, Albert, Lindvall, Mika K, Ma, Sylvia, Möbitz, Henrik, Pecchi, Sabina, Rummel, Gabriele, Shoemaker, Kevin, Trappe, Joerg, Voliva, Charles, Cowan-Jacob, Sandra W, Marzinzik, Andreas L
Format: Article
Language:English
Subjects:
Letter
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00102