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

@article{Karpov2015OptimizationOA,
  title={Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.},
  author={Alexei S. Karpov and Payman Amiri and Cornelia Bellamacina and Marie-Helene Bellance and Werner Breitenstein and Dylan Daniel and Regis Denay and Doriano Fabbro and C{\'e}sar Guti{\'e}rrez Fern{\'a}ndez and Inga Galuba and Stephanie Guerro-Lagasse and Sascha Gutmann and Linda Hinh and Wolfgang Jahnke and Julia Klopp and Albert Kai-Cheong Lai and Mika K Lindvall and Sylvia T Ma and Henrik Moebitz and Sabina Pecchi and Gabriele Rummel and Kevin Shoemaker and J{\"o}rg Trappe and Charles F. Voliva and Sandra W. Cowan-Jacob and Andreas L Marzinzik},
  journal={ACS medicinal chemistry letters},
  year={2015},
  volume={6 7},
  pages={776-81}
}
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… CONTINUE READING

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