A novel dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases

Abstract

Objectives

Inflammasomes induce maturation of the inflammatory cytokines IL‐1β and IL‐18, whose activity is associated with the pathophysiology of a wide range of infectious and inflammatory diseases. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small‐molecule inhibitors to target inflammasome activity and reduce disease‐associated inflammatory burden.

Methods

We examined the therapeutic potential of a novel small‐molecule inhibitor, and associated derivatives, termed ADS032 to target and reduce inflammasome‐mediated inflammation in vivo. In vitro, we characterised ADS032 function, target engagement and specificity.

Results

We describe ADS032 as the first dual NLRP1 and NLRP3 inhibitor. ADS032 is a rapid, reversible and stable inflammasome inhibitor that directly binds both NLRP1 and NLRP3, reducing secretion and maturation of IL‐1β in human‐derived macrophages and bronchial epithelial cells in response to the activation of NLPR1 and NLRP3. ADS032 also reduced NLRP3‐induced ASC speck formation, indicative of targeting inflammasome formation. In vivo, ADS032 reduced IL‐1β and TNF‐α levels in the serum of mice challenged i.p. with LPS and reduced pulmonary inflammation in an acute model of lung silicosis. Critically, ADS032 protected mice from lethal influenza A virus challenge, displayed increased survival and reduced pulmonary inflammation.

Conclusion

ADS032 is the first described dual inflammasome inhibitor and a potential therapeutic to treat both NLRP1‐ and NLRP3‐associated inflammatory diseases and also constitutes a novel tool that allows examination of the role of NLRP1 in human disease.

Abstract

ADS032 represents the first described dual NLRP1 and NLRP3 inflammasome inhibitor, effective in reducing human inflammasome‐mediated inflammation in vitro. ADS032 also effectively reduces both pulmonary and systemic inflammasome‐induced inflammation. Taken together, ADS032 may provide an effective therapeutic strategy to reduce inflammasome‐associated inflammatory diseases.