RIPK1-IN-38 is an orally active inhibitor of RIPK1 with an IC50 of 27 nM. It effectively suppresses the phosphorylation of RIPK1 and its downstream targets RIPK3 and MLKL. Demonstrating anti-necroptosis activity, RIPK1-IN-38 exhibits excellent anti-inflammatory properties in SIRS and GVHD models, making it suitable for research into inflammation and immune-related diseases.

RIPK1:27 nM

RIPK1-IN-38 (Compound 2q), at concentrations of 0.01-10 nM over 24 hours, effectively blocks TSZ/TZ-induced necroptosis in U937, HT-29, and L929 cells, with EC50 values of 0.75 nM, 0.54 nM, and 0.13 nM, respectively. At concentrations of 1.25-5 μM for 72 hours, it exhibits no significant cytotoxicity in HepG2, LX-2, hPBMC, and H9c2 cells. Additionally, RIPK1-IN-38, at 30 nM for 2 hours, completely inhibits the phosphorylation of RIPK1, RIPK3, and MLKL in TSZ-treated HT-29 cells. Furthermore, at 1.25-5 nM over 9 hours, it significantly reduces lactate dehydrogenase (LDH) release in necrotic HT-29 cells.

RIPK1-IN-38, administered orally at doses of 2.5-10 mg/kg as a single dose, significantly reduces inflammation and improves survival rates in a mouse model of TNFα-induced systemic inflammatory response syndrome (SIRS). In a humanized acute graft-versus-host disease (GVHD) model, RIPK1-IN-38 at 15-30 mg/kg, given orally from day 16 to 81, markedly alleviates symptoms and enhances survival rates.