WJH-C19 is an orally active RIPK1 inhibitor with an IC50 of 5.7 nM. WJH-C19 inhibits the RIPK1 / RIPK3 / MLKL signaling axis, blocks RIPK1 phosphorylation, suppresses the phosphorylation of downstream RIPK3 and MLKL, disrupts necrosome formation, and exhibits protective effects against necroptosis ( Apoptosis ) in multiple cell lines. WJH-C19 ameliorates symptoms of inflammatory bowel disease in a mouse colitis model by regulating the necroptosis pathway. WJH-C19 alleviates inflammation and bone destruction in a mouse model of rheumatoid arthritis. WJH-C19 is applicable to research related to inflammatory bowel disease and rheumatoid arthritis [1].
In Vivo, WJH-C19 (1.25-2.5 mg/kg; p.o.; daily; 7 days) potently ameliorates dextran sulfate sodium (DSS, )-induced colitis in female C57BL/6 mice, leading to 47.5% body weight recovery, 42.9% reduction in disease activity index (DAI), and robust inhibition of the RIPK1/RIPK3/MLKL signaling axis[1]. WJH-C19 (10-20 mg/kg; p.o.; daily; 14 days) potently ameliorates complete Freund's adjuvant (CFA, )-induced rheumatoid arthritis in female C57BL/6 mice, reduces paw swelling, joint inflammation and bone destruction, and inhibits the RIPK1/RIPK3/MLKL signaling axis[1].
In Vitro, WJH-C19 (Compound 10e12) (25 h) exerts potent, concentration-dependent protective effects against necroptosis in multiple cell lines, with EC50 values of 0.28 nM in L929 cells, 4.0 nM in HT22 cells, 1.6 nM in HT29 cells, and 2.0 nM in U937 cells; in addition, this compound reduces necroptotic L929 cells in a dose-dependent manner[1]. WJH-C19 potently inhibits the kinase activity of RIPK1, with an IC50 value of 5.7 nM[1]. WJH-C19 (0.5-50 nM) concentration-dependently inhibits the TNFα/z-VAD-FMK (TZ)-induced phosphorylation of RIPK1, RIPK3 and MLKL in L929 cells, as well as the mTNFα/Smac mimetic/z-VAD-FMK (TSZ)-induced phosphorylation in HT29 cells, thereby blocking necrosome formation and the downstream necroptotic signaling pathway[1].
References:
[1]. Wan J, et al. From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization. J Med Chem. 2026;69(3):3252-3288.
In Vivo, WJH-C19 (1.25-2.5 mg/kg; p.o.; daily; 7 days) potently ameliorates dextran sulfate sodium (DSS, )-induced colitis in female C57BL/6 mice, leading to 47.5% body weight recovery, 42.9% reduction in disease activity index (DAI), and robust inhibition of the RIPK1/RIPK3/MLKL signaling axis[1]. WJH-C19 (10-20 mg/kg; p.o.; daily; 14 days) potently ameliorates complete Freund's adjuvant (CFA, )-induced rheumatoid arthritis in female C57BL/6 mice, reduces paw swelling, joint inflammation and bone destruction, and inhibits the RIPK1/RIPK3/MLKL signaling axis[1].
In Vitro, WJH-C19 (Compound 10e12) (25 h) exerts potent, concentration-dependent protective effects against necroptosis in multiple cell lines, with EC50 values of 0.28 nM in L929 cells, 4.0 nM in HT22 cells, 1.6 nM in HT29 cells, and 2.0 nM in U937 cells; in addition, this compound reduces necroptotic L929 cells in a dose-dependent manner[1]. WJH-C19 potently inhibits the kinase activity of RIPK1, with an IC50 value of 5.7 nM[1]. WJH-C19 (0.5-50 nM) concentration-dependently inhibits the TNFα/z-VAD-FMK (TZ)-induced phosphorylation of RIPK1, RIPK3 and MLKL in L929 cells, as well as the mTNFα/Smac mimetic/z-VAD-FMK (TSZ)-induced phosphorylation in HT29 cells, thereby blocking necrosome formation and the downstream necroptotic signaling pathway[1].
References:
[1]. Wan J, et al. From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization. J Med Chem. 2026;69(3):3252-3288.