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

Karpov, Alexei, Bellamacina, Cornelia, Bellance, Marie-Helene, Breitenstein, Werner, Denay, Regis, Fernandez, Cesar, Galuba, Inga, Gutmann, Sascha, Jahnke, Wolfgang, Klopp, Julia, Guerro-Lagasse, Stephanie, Lindvall, Mika, Ma, Sylvia, Moebitz, Henrik, Rummel, Gabriele, Trappe, Joerg, Jacob, Sandra and Marzinzik, Andreas (2015) Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor. ACS Medicinal Chemistry Letters, 6 (7). pp. 776-781. ISSN 1948-58751948-5875


Most kinase inhibitors discovered to date block the ATP binding site which is highly conserved among different kinases and, as a result, such compounds very often suffer from lack of kinase selectivity. Discovery of inhibitors targeting novel allosteric kinase sites is still considered very challenging. In our previous report we described discovery of allosteric inhibitors, such as 1, targeting PAK1 kinase. Herein we report our structure-based optimization strategy yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was co-crystallized 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.

Item Type: Article
Date Deposited: 13 Oct 2015 13:11
Last Modified: 04 Jul 2016 23:45


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