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The p38 pathway has been at the center of interest for anti-inflammatory drug discovery for many years as it is crucial for the biosynthesis of TNF-α, IL-1β and other mediators. Most of the anti-inflammatory effects of p38 inhibition are mediated through MAPK-activated protein kinase-2 (MK2), a direct downstream target of p38, which makes MK2 a very interesting drug target. Within the last 5 years, several classes of low-molecular-weight MK2 inhibitors were disclosed in the patent and primary literature. Advanced compounds could be optimized to nanomolar potencies and inhibit TNF-α release, as well as the phosphorylation of the MK2 substrate heat-shock protein 27 in cellular assays. This article will review the recent progress in this field and will highlight and discuss the most promising compound series disclosed so far.
Schlapbach et al. (Thu,) studied this question.