| Autor: |
Stephanie Guerro-Lagasse, Andreas Marzinzik, Sandra W. Cowan-Jacob, Linda Hinh, César Fernández, Julia Klopp, Alexei S. Karpov, Sabina Pecchi, Inga Galuba, Henrik Möbitz, Sylvia Ma, Kevin Shoemaker, Payman Amiri, Marie-Helene Bellance, Werner Breitenstein, Joerg Trappe, Dylan Daniel, Gabriele Rummel, Mika Lindvall, Charles Voliva, Cornelia Bellamacina, Wolfgang Jahnke, Doriano Fabbro, Sascha Gutmann, Albert Lai, Regis Denay |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
|
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
