Repurposing AZD-7762 as a novel direct NLRP3 inhibitor for the treatment of inflammatory diseases

The NLRP3 inflammasome is a critical component of innate immunity, and its aberrant activation is implicated in the pathogenesis of various inflammatory diseases, including cryopyrin-associated periodic syndrome (CAPS), sepsis, inflammatory bowel disease, and type 2 diabetes. Although several NLRP3 inhibitors have entered clinical trials, none have been approved by the FDA to date, highlighting an urgent need for novel, safe, and efficient drug candidates. AZD-7762 is a well-known inhibitor of checkpoint kinase 1/2 (Chk1/2) primarily investigated for its role in enhancing Cancer chemosensitivity; however, its function in inflammation remains unknown. Here, we identify AZD-7762 as a highly potent and selective direct inhibitor of the NLRP3 inflammasome. Mechanistically, AZD-7762 directly binds to the ATP-binding site of the NLRP3 NACHT domain, thereby inhibiting NLRP3 ATPase activity, oligomerization, and subsequent inflammasome assembly. Importantly, pharmacological administration of AZD-7762 significantly ameliorated disease severity in mouse models of NLRP3-driven diseases, including lipopolysaccharide (LPS)-induced systemic inflammation and dextran sulfate sodium (DSS)-induced colitis. Our findings reveal a novel function for AZD-7762 and suggest that it is a promising therapeutic candidate for the treatment of NLRP3-related inflammatory disorders.