Inflammasomes are protein complexes that are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18.  NLRP3 is a drug target of significant interest to the pharmaceutical industry. It has the potential for the treatment of several inflammatory diseases including cancer, autoimmune diseases, metabolic disorders, cardiovascular disease, CNS diseases, and infectious diseases including COVID-19. The activation of the canonical NLRP3 inflammasome pathway requires two stages. In this study, MCC7840, a sulfonylurea, is a potent and selective inhibitor of NLRP3 inflammasome. It has the potential for the research of inflammatory diseases. Moreover, MCC7840 is an MCC950 analog. It also shows useful activity in the inhibition of activation of the NLRP3 inflammasome, with an IC₅₀ of <100 nM.

The primary signal includes activation of NF-κB mediated by MYD88 by binding of PAMPs and DAMPs to TLR, and its translocation to the nucleus to undergo transcription and translation of NLRP3 inflammasome components as well as pro-inflammatory cytokines. Secondary signals result in NLRP3 inflammasome activation. It includes ROS from mitochondrial disruption, cathepsins, VRAC efflux of anions and osmolytes, and Ca²⁺ influx. In addition, the oligomerization and activation of NLRP3 inflammasome results in cleavage of pro-inflammatory cytokines proIL-1β and proIL-18. They give the mature forms inflammatory cytokines IL-1β and IL-18. At last, they cause inflammation.

In summary, the NLRP3 inflammasome has been the focus of drug discovery research due to its involvement in several inflammatory diseases. MCC7840 is a potent and selective inhibitor of NLRP3 inflammasome. Thus, it has the potential for the research of inflammatory diseases.

Reference:

El-Sharkawy LY, et, al. 2020 Nov 25;25(23):5533.