UH15-38 is a potent, specific receptor interacting protein kinase 3 (RIPK3) inhibitor with IC50 of 20 nM in NanoBRET assays, potently and selectively blocks IAV-triggered necroptosis in alveolar epithelial cells in vivo.
UH15-38 blocks TNF-induced necroptosis in primary mouse embryonic fibroblasts (MEFs) with IC50 of 98 nM, 8.5-fold lower than those of GSK′843 (IC50 = 843 nM) and around sixfold lower than those of GSK′872.
UH15-38 prevents phosphorylation of MLKL following necroptotic stimulation by TNF, also robustly inhibits necroptosis in a panel of human and mouse cell lines.
UH15-38 exhibits selectivity for RIPK3-driven necroptotic cell death, displays no significant activity against RIPK1 kinase-driven caspase-8-dependent cell death, also does not inhibit gasdermin D cleavage or pyroptosis upon canonical activation of the NLRP3 inflammasome by nigericin.
UH15-38 does not significantly inhibit a panel of 50 critical protein targets, as well as clean profile against a panel of 90 non-mutant human kinases (DiscoverX KinomeScan).
UH15-38 (1 uM) selectively blocks IAV-induced necroptosis in type I alveolar epithelial cells (AECs), protects type I AECs from canonical TNF-induced necroptosis with IC50 of 114 nM.
UH15-38 a highly potent inhibitor of IAV-induced necroptosis in primary type I AECs (IC50 =39.5 nM) and primary MEFs (IC50 =51.9 nM), respectively.
UH15-38 (30 mg/kg) ameliorates lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, prevents necroptosis, inflammation, and injury in IAV-infected lungs.
UH15-38 does not alter the extent of virus replication and spread or the rate of virus clearance from infected lungs.
