4 research outputs found
Optimized Target Residence Time: Typeâ Inhibitors for p38 MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine
Skepinone-L was recently reported to be a p38 MAP kinase inhibitor with high potency and excellent selectivity inâ
vitro and inâ
vivo. However, this class of compounds still act as fully ATP-competitive Typeâ
I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Typeâ
â
binders for p38 MAP kinase. â
formula inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regionsâ
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
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 âdeep pocketâ, 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 âdeep pocketâ in the DFG-out conformation,
interactions with the DFG-motif in the in-conformation could be observed
by protein X-ray crystallography
Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity
p38α mitogen-activated protein (MAP) kinase is
a main target
in drug research concerning inflammatory diseases. Nevertheless, no
inhibitor of p38α MAP kinase has been introduced to the market.
This might be attributed to the fact that there is no inhibitor which
combines outstanding activity in biological systems and selectivity.
Herein an approach to the development of such inhibitors on the basis
of the highly selective molecular probe Skepinone-L is described.
Introduction of a âdeep pocketâ moiety addressing the
DFG motif led to an increased activity of the compounds. Hydrophilic
moieties, addressing the solvent-exposed area adjacent to hydrophilic
region II, conserved a high activity of the compounds in a whole blood
assay. Combined with their outstanding selectivity and low ATP competitiveness,
these inhibitors are very interesting candidates for use in biological
systems and in therapy