Skepinone-L was recently reported to be a p38 MAP kinase inhibitor with high potency and excellent selectivity invitro and invivo. However, this class of compounds still act as fully ATP-competitive TypeI binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first TypeI1/2 binders for p38 MAP kinase. TypeI1/2 inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regionsI 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.