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Optimized Target Residence Time: Type I 1 / 2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R‐Spine
Author(s) -
Wentsch Heike K.,
Walter Niklas M.,
Bührmann Mike,
MayerWrangowski Svenja,
Rauh Daniel,
Zaman Guido J. R.,
WillemsenSeegers Nicole,
Buijsman Rogier C.,
Henning Melanie,
Dauch Daniel,
Zender Lars,
Laufer Stefan
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201701185
Subject(s) - potency , chemistry , in vivo , kinase , binding site , in vitro , enzyme , residence time (fluid dynamics) , selectivity , biochemistry , stereochemistry , biophysics , biology , genetics , geotechnical engineering , engineering , catalysis
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.