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