Functional Characterization of an Arylsulfonamide-Based\nSmall-Molecule Inhibitor of the NLRP3 Inflammasome

Considerable evidence\nindicates that the NOD-like receptor family\npyrin domain-containing 3 (NLRP3) inflammasome plays key roles in\nhuman pathophysiology, suggesting it as a potential drug target. Currently,\nstudies have yet to develop compounds that are promising therapeutics\nin the clinic by targeting the NLRP3 inflammasome. Herein, we aim\nto further biologically characterize a previously identified small-molecule\ninhibitor of the NLRP3 inflammasome from our group, YM-I-26, to confirm\nits functional activities. We showed that YM-I-26 is highly selective\ntoward the NLRP3 inflammasome and binds to NLRP3 directly. A systemic\nanalysis revealed YM-I-26 with inflammation-related and immunomodulatory\nactivities by the Eurofins BioMAP Diversity PLUS panel. In addition,\nstudies using the mouse microglia BV2 cell model demonstrated that\nYM-I-26 is not cytotoxic, improved the phagocytotic functions of BV2\ncells toward beta-amyloid, and suppressed the production of cytokines\nof IL-1β and IL-10 upon the activation of the NLRP3 inflammasome.\nCollectively, our studies support the functional activities of YM-I-26\nas a NLRP3 inhibitor in physiologically relevant cell models, and\nwarrant future studies of YM-I-26 and its analogs to advance the drug\ndevelopment as potential therapeutics.