RIPK2-IN-8 is an orally active and highly selective RIPK2 inhibitor with an IC50 of 11 nM. It exhibits greater selectivity for RIPK2 over RIPK1 (IC50 > 30,000 nM) and has moderate inhibitory effects on RIPK3 (IC50 = 44.61 nM). RIPK2-IN-8 exerts anti-inflammatory effects by inhibiting the NOD2-RIPK2 signaling pathway and the expression of inflammatory cytokines IL-6 and TNFα. Additionally, in models of acute liver injury (ALI), RIPK2-IN-8 demonstrates both anti-inflammatory and hepatoprotective effects, making it useful for ALI research.

RIPK2:11 nM

RIPK2-IN-8 (Compound HY3) at concentrations of 0-10 μM for 0.5-6 hours, delays the activation of NF-kB and MAPK in L18-MDP stimulated THP-1 cells without affecting protein expression or cell viability. At 1 μM, RIPK2-IN-8 exhibits minimal inhibitory activity against inflammation-related kinases such as BTK, FLT3, JNK2α2, SAPK3, MSK1, and MAPKAP-K2. It shows low cytotoxicity in H9C2 cells with an IC50 greater than 40 μM. Additionally, RIPK2-IN-8 inhibits IL-8 production in MDP-stimulated THP-1 cells, with an IC50 of 29 nM.

RIPK2-IN-8 (Compound HY3) [7.5-30 mg/kg, orally, single dose] suppresses RIPK2 kinase activity in an MDP-induced peritonitis mouse model, which in turn blocks the activation of downstream inflammatory signaling and subsequently affects the synthesis and release of cytokine IL-6. Additionally, RIPK2-IN-8 [5-20 mg/kg, orally, single dose] demonstrates hepatoprotective effects in an Acetaminophen (APAP)-induced acute liver injury (ALI) model by inhibiting the expression of inflammatory cytokines, thereby reducing serum inflammatory markers and mitigating liver damage.