Discovery of a Novel Oral Proteasome Inhibitor to Block NLRP3 Inflammasome Activation with Anti-inflammation Activity

NLRP3 inflammasome activation plays a critical role in inflammation-related disorders. More small-molecule entities are needed to study the mechanism of NLRP3 inflammasome activation and to validate the efficacy and safety of the NLRP3 pathway. Herein, we report the discovery of an orally bioavailable proteasome inhibitor NIC-0102 (27) that specifically prevents NLRP3 inflammasome activation but has no effect on NLRC4 or AIM2 inflammasomes. In vitro studies revealed that NIC-0102 induced the polyubiquitination of NLRP3, interfered with the NLRP3–ASC interaction, and blocked ASC oligomerization, thereby resulting in the inhibition of NLRP3 inflammasome activation. In addition, NIC-0102 also inhibited the production of pro-IL-1β. Importantly, NIC-0102 showed potent anti-inflammatory effects on DSS-induced ulcerative colitis model in vivo. As a result of these studies, a potential small molecule is identified to demonstrate the possible link between the proteasome and NLRP3 pathway, which supports further exploration of potentially druggable nodes to modulate NLRP3 inflammasome activation.