Targeting the hinge glycine flip and the activation loop: novel approach to potent p38α inhibitors.
The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry,  Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Kathrin E
KE
Martz
Angelika
A
Dorn
Benjamin
B
Baur
Verena
V
Schattel
Márcia I
MI
Goettert
Svenja C
SC
Mayer-Wrangowski
Daniel
D
Rauh
Stefan A
SA
Laufer
D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14; D005998:Glycine