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

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• 作者：Alexei S. Karpov ; Payman Amiri ; Cornelia Bellamacina ; Marie-Helene Bellance ; Werner Breitenstein ; Dylan Daniel ; Regis Denay ; Doriano Fabbro ; Cesar Fernandez ; Inga Galuba ; Stephanie Guerro-Lagasse ; Sascha Gutmann ; Linda Hinh ; Wolfgang Jahnke ; Julia Klopp ; Albert Lai ; Mika K. Lindvall ; Sylvia Ma ; Henrik M枚bitz ; Sabina Pecchi ; Gabriele Rummel ; Kevin Shoemaker ; Joerg Trappe ; Charles Voliva ; Sandra W. Cowan-Jacob ; Andreas L. Marzinzik
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：6
• 期：7
• 页码：776-781
• 全文大小：360K
• ISSN：1948-5875

文摘

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.