An RRx-001 Analogue With Potent Anti-NLRP3 Inflammasome Activity but Without High-Energy Nitro Functional Groups

Abstract

NLRP3 inflammasome is involved in the pathology of multiple human inflammatory diseases but there are still no clinically available medications targeting the NLRP3 inflammasome. We have previously identified RRx-001 as a highly selective and potent NLRP3 inhibitor, however, it contains high-energy nitro functional groups and may cause potential processing problems and generates highly toxic oxidants. Here, we show that compound 149-01, an RRx-001 analogue without high-energy nitro functional groups, is a potent, specific and covalent NLRP3 inhibitor. Mechanistically, 149-01 binds directly to cysteine 409 of NLRP3 to block the NEK7-NLRP3 interaction, thereby preventing NLRP3 inflammasome complex assembly and activation. Furthermore, treatment with 149-01 effectively alleviate the severity of several inflammatory diseases in mice, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate crystals (MSU)-induced peritonitis and experimental autoimmune encephalomyelitis (EAE). Thus, our results indicate that 149-01 is a potential lead for developing therapeutic agent for NLRP3-related inflammatory diseases.

Entrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7

“… 60 Several inhibitors, such as manoalide, oridonin, and RRx-001 and its analog have been reported previously to bind to NLRP3 to block its interaction with NEK7. 20 , 49 , 61 , 62 In this study, our results demonstrated that the FDA-approved clinical anti-cancer agent ENB directly binds to NEK7 at R121, a key residue located at the interaction interface between NEK7 and NLRP3, 8 to significantly inhibit NLRP3-NEK7 interaction and inflammasome activation. Thus, our results provide evidence showing that ENB could be used as a candidate drug to control NLRP3 inflammasome activation by targeting NEK7.…”

Role of NLRP3 Inflammasome in Rheumatoid Arthritis

“…However, RRX001 contains high-energy nitro functional groups, which may cause drug toxicity. Compound 149-01, an analog of RRX001 without high-energy nitro functional groups, was recently identified as a potent and specific NLRP3 inhibitor that inhibits NLRP3 activation and attenuates inflammatory responses in vivo and vitro by preventing NLRP3 from binding to NEK7 ( 123 ). Licochalcone B (LicoB), a major component of traditional medicinal herb licorice, was also found to disturb the interaction between NLRP3 and NEK7, thus inhibiting NLRP3 activation ( 124 ).…”