Discovery of a novel orally bioavailable NLRP3 inflammasome inhibitor, TTS-X, for potential treatment of inflammatory bowel disease

Abstract Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory diseases, including inflammatory bowel disease. Herein, we discovered a series of potent and selective NLRP3 inhibitors with non-sulfonylurea analogue. TTS-X, lead compound identified from this series, was found to bind directly to NLRP3 in cells by chemical proteomics study. It exhibited potent and specific inhibition against NLRP3 activation and IL-1β production in human macrophage and whole blood. In addition, in an acute peritonitis model, TTS-X inhibited NLRP3 dependent IL-1β production in a dose-dependent manner. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, it demonstrated significant anti-inflammatory activity after oral administration. Collectively, these results suggest that TTS-X is a potent and oral bioavailable NLRP3 inhibitor with biological activity in vivo. Further characterization of this lead compound is under way for potential treatment of inflammatory bowel disease and other NLRP3-driven diseases