Moving Beyond MCC950: Discovery of a Novel NLRP3 Inhibitor Series Using a Scaffold Hopping Approach

<jats:p>The NLRP3 inflammasome is a key part of the innate immune system, and the ability to modulate it represents a huge opportunity for both drug discovery and biomedical research. However, the development of a structurally diverse toolkit of inhibitors has been hampered by toxicity liabilities linked to key scaffolds such as the benchmark compound MCC950. To address this, we employed a virtual scaffold-hopping approach to identify new NLRP3 inhibitors lacking the hexahydro-s-indacene and sulfonylurea moieties commonly found in other classes. This identified a tertiary sulfonamide compound series showing promising activity, with compound 10 displaying NLRP3 inhibition at micromolar concentrations across multiple readouts, in both mouse and human cell lines. This series represents a new chemotype with an accessible synthetic route for optimisation that can facilitate further study of NLRP3 biology.</jats:p>