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Screening Assays to Characterize Novel Endothelial Regulators Involved in the Inflammatory Response
Published on: September 15, 2017
CH7450924, a KEAP1-NRF2 interaction inhibitor, ameliorates LPS-induced multiple organ dysfunction via inflammatory
Masaki Hoshino1, Yukari Yasui2, Shun Mitsumata2
1Chugai Research Institute for Medical Science, Inc., Kanagawa, Japan. hoshinomsk@chugai-pharm.co.jp.
Abstract:
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.
Insights
Multiple organ dysfunction syndrome (MODS) is a severe condition. Activating Nuclear factor erythroid 2-related factor 2 (NRF2) with CH7450924 shows promise in treating MODS by reducing inflammation and protecting organs.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Multiple organ dysfunction syndrome (MODS) is a leading cause of mortality worldwide with high unmet medical needs.
- Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular defense pathways, with potential therapeutic implications for MODS.
- The specific role of NRF2 in ameliorating MODS and the efficacy of NRF2 activators remain largely unexplored.
Purpose of the Study:
- To identify and characterize a novel inhibitor of the kelch-like ECH-associated protein 1 (KEAP1)-NRF2 interaction.
- To evaluate the therapeutic efficacy of the novel compound CH7450924 in preclinical models of lipopolysaccharide (LPS)-induced MODS.
- To elucidate the protective mechanisms of NRF2 activation in MODS, focusing on anti-inflammatory and organ-protective effects.
Main Methods:
- Crystallography was employed to analyze the binding of CH7450924 to KEAP1.
- Binding and inhibition assays were performed to assess the selectivity of CH7450924 as a KEAP1-NRF2 inhibitor.
- Therapeutic efficacy was evaluated in an LPS-induced MODS mouse model, assessing survival, inflammatory markers, organ function, microcirculation, and histopathology.
Main Results:
- CH7450924 demonstrated selective, non-covalent, competitive inhibition of the KEAP1-NRF2 interaction.
- Treatment with CH7450924 significantly reduced mortality rates in the MODS model.
- CH7450924 decreased key inflammatory cytokines (IL-6, IL-1β, TNFα), improved kidney and liver function, enhanced microcirculation, and reduced endothelial damage in multiple organs.
Conclusions:
- NRF2 activation is a critical therapeutic strategy for managing MODS.
- CH7450924, a potent and selective NRF2 activator, effectively ameliorates MODS.
- The protective effects of CH7450924 are attributed to its anti-inflammatory properties and ability to prevent endothelial damage and organ dysfunction.
