Inhibition of p38α MAPK-MK2 axis alleviate inflammatory response in various inflammation-related disease models

Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated by p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. Preclinical studies indicate that targeting MK2 may be a much safer approach than blocking p38a MAPK activation because that dissect the pathway downstream of p38α MAPK without affecting additional cellular functions. 141-A was identified as a highly potent and selective p38α MAPK-MK2 allosteric inhibitor that exhibited nanomolar-level inhibition on p38α MAPK activation of MK2 while sparing the p38α MAPK activation of ATF2 and PRAK. 141-A potently reduced various cytokine production (TNFα, IL-1β, IL-6, IL-8 and IL-17) in human peripheral blood mononuclear cells (PBMC) and displayed excellent efficacy in adjuvant-induced arthritis (AIA), psoriasis and MSU-induced air pouch rat models with 1/6 of the systematic exposure of CDD450. The compound exhibits favorable physicochemical and pharmacokinetic properties, along with an excellent preclinical toxicity profile, which may enhance therapeutic efficacy without causing side effects. 141-A is currently under IND-enabling studies and P1 trial is planned in early 2025.