Optimized Target Residence Time: Type I1/2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine
Wentsch, H.K. and Walter, N.M. and Bührmann, M. and Mayer-Wrangowski, S. and Rauh, D. and Zaman, G.J.R. and Willemsen-Seegers, N. and Buijsman, R.C. and Henning, M. and Dauch, D. and Zender, L. and Laufer, S.
ANGEWANDTE CHEMIE - INTERNATIONAL EDITION
Volume: 56 Pages: 5363-5367
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 I 1/2 binders for p38α MAP kinase. Type I 1/2 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. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim