Ofirnoflast: a first-in-class NEK7-targeted inhibitor of the NLRP3 inflammasome.

Ofirnoflast is a first-in-class, orally bioavailable NEK7 inhibitor currently undergoing Phase 2 clinical evaluation. It disrupts NLRP3 inflammasome assembly by targeting NEK7's scaffolding function-blocking complex formation independently of NLRP3 activation status, upstream of caspase activation, pyroptosis, and inflammatory cytokine release. This mechanism offers a novel therapeutic approach for chronic inflammation. Unlike NSAIDs, corticosteroids, cytokine-neutralising biologics, and NLRP3-directed small molecules-which are frequently limited by off-target effects, immunosuppression, or incomplete efficacy-ofirnoflast provides a targeted approach with fewer anticipated liabilities. We demonstrate that ofirnoflast engages an allosteric site adjacent to NEK7's ATP-binding pocket, inducing conformational shifts that impair its scaffolding function. In THP-1 macrophages and iPSC-derived microglia, ofirnoflast suppresses ASC specks, IL-1β release, and pyroptotic cell death. Biophysical assays and molecular dynamics simulations confirm that ofirnoflast stabilises NEK7 in a unique conformation and suggest a type-2 kinase-inhibitor binding mode. In vivo, ofirnoflast exhibits oral bioavailability, achieving systemic exposures well above cellular potency thresholds. In a DSS-induced colitis model, treatment significantly reduces cytokine levels and improves phsyiological outcomes. Collectively, these findings validate NEK7 as a druggable checkpoint for NLRP3 inflammasome control and position Ofirnoflast as a mechanistically distinct, clinically advanced candidate for treating inflammation driven by aberrant inflammasome activation.