molecules of the month

Context. CC-99677 (BMS) is an oral, covalent MAPK–activated protein kinase-2 (MK2) inhibitor being developed for autoimmune diseases. Although p38 is the most heralded member of the p38-MAPK signaling pathway, one that mediates the release of pro-inflammatory cytokines and is implicated in several inflammatory diseases, attempts to directly inhibit the kinase have been largely unsuccessful. Notably, these agents have been associated with a lack of sustained efficacy (tachyphylaxis), potentially stemming from their inhibition of other key proteins involved in feedback regulation of the signaling pathway. Consequently, targeting MK2, a downstream target of p38, is hypothesized as a strategy to circumvent this compensatory feedback mechanism. CC-99677 was found by BMS scientists to mediate a cytokine inhibitory profile different from that of previously…