RESUMO
Skepinone-L was recently reported to be a p38α 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 I1/2 binders for p38α MAP kinase. Typeâ I1/2 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.
Assuntos
Dibenzocicloeptenos/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Dibenzocicloeptenos/síntese química , Dibenzocicloeptenos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Fatores de TempoRESUMO
We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.