3 years ago

Optimized Target Residence Time: Type I1/2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine

Optimized Target Residence Time: Type I1/2
 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine
Svenja Mayer-Wrangowski, Melanie Henning, Nicole Willemsen-Seegers, Guido J. R. Zaman, Rogier C. Buijsman, Daniel Dauch, Mike Bührmann, Daniel Rauh, Stefan Laufer, Heike K. Wentsch, Niklas M. Walter, Lars Zender
Skepinone-L was recently reported to be a p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, this class of compounds still act as fully ATP-competitive Type I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Type I1/2 binders for p38α MAP kinase. Type I1/2 inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regions I and II. This design approach leads to prolonged target residence time, binding to both the active and inactive states of the kinase, excellent selectivity, excellent potency on the enzyme level, and low nanomolar activity in a human whole blood assay. This promising binding mode is proven by X-ray crystallography. Staying power: A novel class of substituted dibenzosuberones combines high selectivity and potency in vitro with prolonged residence times and act as type I1/2 inhibitors of the enzyme p38α MAP kinase. The concept of the additional R-spine interaction was successfully transferred to the already very potent Skepinone-L scaffold.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201701185

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