Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis

Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis

“…MCC950 has been shown to interact with the Walker B motif in ATPase, , exhibiting excellent anti-inflammatory activity. However, the phase II clinical trial of MCC950 was terminated due to hepatotoxicity, which might be attributed to the high daily dose of 1.2 g and its metabolically reactive furan fragment. , Most reported small molecules exert their anti-inflammatory activity by targeting the NACHT domain of the NLRP3 protein. With the elucidation of the crystal structure of the NLRP3-NEK7 protein complex, it has been revealed that the LRR domain of the NLRP3 protein is a critical region mediating the interaction between NLRP3 and NEK7 (PDB ID: 6npy).…”

Novel chemotype NLRP3 inhibitors that target the CRID3-binding pocket with high potency

“…Furthermore, carbonic anhydrase II (CA II) was recently identified as an off-target for this compound class ( Kennedy et al, 2021 ). Another concern is that early clinical development of CRID3 in a phase 2 clinical trial for the treatment of rheumatoid arthritis was discontinued, reportedly because of CRID3 dosing in healthy volunteers causing drug-induced liver injury ( Shah et al, 2015 ; Kennedy et al, 2021 ; Li et al, 2023 ). Therefore, the discovery of novel potent and selective NLRP3-targeted inhibitors with distinctive chemical scaffolds is urgently needed to open up additional avenues for clinical development of NLRP3-targeted therapeutics.…”

Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis

“…The development of inhibitors targeting the NLRP3 inflammasome has received widespread attention in the past decade. , Several drug candidates have been identified through chemical synthesis or via screening natural products and their derivatives; some of them have demonstrated potential efficacy in treating diseases in both in vitro and in vivo models, with a few even progressing to clinical trials. ,, Currently, several NLRP3 inhibitors, including MCC950, OLT1177, somalix, IFM-2427, NT-0167, ZYIL-1, IZD-174, IZD-334, and RRx-001, have entered clinical trials, ,− but none of them have been approved for marketing. MCC950 is the most potent NLRP3 inhibitor among them; it directly targets the Walker A of the NACHT domain and stabilizes the inactive state of NACHT and LRR domains. − However, MCC950 was terminated in the phase II clinical trial due to the drug induced liver injury (DILI) .…”