Targeting the Hinge Glycine
Flip and the Activation
Loop: Novel Approach to Potent p38α Inhibitors
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Abstract
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<sub>50</sub> 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