title: Optimized Target Residence Time: Type I1/2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Heike K
authors.initials: HK
authors.lastname: Wentsch
authors.affiliation: Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Niklas M
authors.initials: NM
authors.lastname: Walter
authors.affiliation: Faculty of Chemistry and Chemical Biology, Technische Universität Dortmund, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Bührmann
authors.affiliation: Faculty of Chemistry and Chemical Biology, Technische Universität Dortmund, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Mayer-Wrangowski
authors.affiliation: Faculty of Chemistry and Chemical Biology, Technische Universität Dortmund, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.affiliation: Netherlands Translational Research Center B.V. (NTRC), Oss, The Netherlands.
authors.forename: Guido J R
authors.initials: GJR
authors.lastname: Zaman
authors.affiliation: Netherlands Translational Research Center B.V. (NTRC), Oss, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Willemsen-Seegers
authors.affiliation: Netherlands Translational Research Center B.V. (NTRC), Oss, The Netherlands.
authors.forename: Rogier C
authors.initials: RC
authors.lastname: Buijsman
authors.affiliation: Department of Internal Medicine VIII, University Hospital Tübingen (Germany).|Institute of Physiology, Department of Physiology I, Eberhard Karls Universität Tübingen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Henning
authors.affiliation: Department of Internal Medicine VIII, University Hospital Tübingen (Germany).|Institute of Physiology, Department of Physiology I, Eberhard Karls Universität Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.affiliation: Department of Internal Medicine VIII, University Hospital Tübingen (Germany).|Institute of Physiology, Department of Physiology I, Eberhard Karls Universität Tübingen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D003986:Dibenzocycloheptenes; D047428:Protein Kinase Inhibitors; C572387:skepinone-L; D048308:Mitogen-Activated Protein Kinase 14
keywords: drug design; inhibitors; kinases; residence time