SZM-1209

SZM-1209 is an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1).¹ It selectively binds to RIPK1 over RIPK3 (K_ds = 85 and >10,000 nM, respectively) and inhibits necrosome formation and phosphorylation of RIPK1 induced by TNF-α, SM-164 , and Z-VAD-FMK in HT-29 cells (EC₅₀ = 22.4 nM). SMZ-1209 (10 and 20 mg/kg) decreases reductions in body temperature and improves survival in a mouse model of systemic inflammatory response syndrome (SIRS) induced by TNF-α and Z-VAD-FMK. It also reduces lung RIPK1 phosphorylation, IL-6 and TNF-α levels, and total protein content, as well as decreases the number of hemorrhagic sites and congestion edema, in a mouse model of acute lung injury (ALI) induced by short-term intratracheal exposure to 4-(N-nitrosometlamino)-1-(3-pyridyl)-1-butanone .