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Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action.

The Journal of experimental medicine

Authors: Kevin Wilhelmsen, Aditi Deshpande, Sarah Tronnes, Maitriyee Mahanta, Matthew Banicki, Mary Cochran, Samantha Cowdin, Kristen Fortney, George Hartman, Robert E Hughes, Rusty Montgomery, Claudia P Portillo, Paul Rubin, Taiz Salazar, Yan Wang, Shijun Yan, Barry A Morgan, Assem Duisembekova, Romane Riou, Michael Marleaux, Inga V Hochheiser, Hannes Buthmann, Dominic Ferber, Jane Torp, Wei Wang, Melanie Cranston, Chloe M McKee, Thea J Mawhinney, Emma C McKay, Fehime K Eroglu, Jasmin Kümmerle-Deschner, Alexander N R Weber, Bénédicte F Py, Matthias Geyer, Rebecca C Coll

The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases.

© 2025 Wilhelmsen et al.

PMID: 40892070

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