CH7450924, a KEAP1-NRF2 interaction inhibitor, ameliorates LPS-induced multiple organ dysfunction via inflammatory...

Multiple organ dysfunction syndrome (MODS) claims a life every few seconds worldwide and is a severe condition that can affect people of all ages. Despite the availability of various treatments, the unmet medical needs remain high. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key molecule involved in biological protection and is expected to be beneficial for MODS, but its role in ameliorating MODS remains unknown. We identified a novel kelch-like ECH-associated protein 1 (KEAP1)-NRF2 protein-protein interaction inhibitor, CH7450924, and evaluated its efficacy in lipopolysaccharide (LPS)-induced MODS models. To characterize our compound, we analyzed CH7450924 binding to KEAP1 by crystallography. Comprehensive binding and inhibition experiments were conducted to evaluate selectivity. Subsequently, we assessed its therapeutic effects using an LPS-induced MODS mouse model. In the MODS model, survival rate, inflammatory markers, organ function, microcirculation, and histopathology were assessed. The results demonstrated that CH7450924 bound non-covalently to KEAP1 and competitively inhibited the KEAP1-NRF2 binding with high selectivity. In the MODS model, CH7450924 significantly ameliorated the mortality rate. CH7450924 significantly decreased plasma IL-6, IL-1β, and TNFα and suppressed inflammatory cytokine mRNA expression in kidney and liver. CH7450924 improved kidney function and liver injury as indicated by plasma biochemistry. While not affecting blood pressure or heart rate, CH7450924 significantly improved peripheral blood flow in the ear. CH7450924 also significantly increased platelet count and reduced plasma PAI-1. Endothelial damage markers were also reduced in kidney and liver. In a lung injury model induced by intratracheal LPS injection, CH7450924 significantly reduced inflammation, prevented structural damage, and improved respiratory function. In conclusion, this study reveals that NRF2 activation is critical for the treatment for MODS. CH7450924, a highly potent and selective NRF2 activator, ameliorated MODS by protecting kidney, liver, and lung through its anti-inflammatory properties and its ability to protect against endothelial damage and organ dysfunction.