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.