Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation.

Summary

High-throughput screening identified LOC14, an isothiazolinone inhibitor that binds the NLRP3 LRR domain and suppresses both MCC950-sensitive and -resistant NLRP3 variants. LOC14 reduced inflammation in vivo across colitis, sepsis, and psoriasis models, and structure–activity data implicated the isothiazol-3(2H)-one carbonyl oxygen as essential for activity.

Key Findings

• LOC14, an isothiazolinone-containing small molecule, selectively inhibits NLRP3 by binding to or near its LRR domain.
• LOC14 suppresses both MCC950 (CRID3)-responsive and -non-responsive hyperactive/gain-of-function NLRP3 variants.
• The carbonyl oxygen of the isothiazol-3(2H)-one moiety is critical for inhibitory activity.
• In vivo anti-inflammatory efficacy was demonstrated in mouse models of colitis, sepsis, and psoriasis.

Clinical Implications

Although preclinical, LRR-domain–targeted NLRP3 inhibitors could broaden treatment options for NLRP3-driven conditions including sepsis; safety, PK, and human validation are needed.

Limitations

• Lack of human data; pharmacokinetics/toxicology not comprehensively characterized.
• Isothiazolinones are reactive electrophiles, raising potential off-target/toxicity concerns.

Future Directions

Optimize potency and safety, perform PK/PD and toxicity studies, evaluate efficacy in polymicrobial sepsis (e.g., CLP) and define translational biomarkers for clinical development.