Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation
Abstract
The NLRP3 inflammasome is a key driver in inflammatory, infectious, metabolic, and neurodegenerative diseases. Although the NLRP3 inhibitor CRID3 (also known as MCC950) exhibits potent activity, it cannot inhibit several hyperactive NLRP3 mutations associated with autoinflammatory syndromes and has not progressed clinically, underscoring the need for the development of new NLRP3 inhibitors. Through a high-throughput screening, we identified LOC14, an isothiazolinone-containing small molecule, as a selective NLRP3 inhibitor. Distinct from CRID3, which targets the NACHT domain, LOC14 binds to or near the LRR domain of NLRP3 and inhibits both CRID3-responsive and CRID3-non-responsive hyperactive or gain-of-function NLRP3 variants. Furthermore, we identified that the carbonyl oxygen of the isothiazol-3(2H)-one moiety is critical for inhibitory activity. In vivo, LOC14 exerted anti-inflammatory activity in mouse models of colitis, sepsis, and psoriasis, demonstrating broad physiological and therapeutic relevance. Our findings highlight isothiazolinone-containing compounds as selective NLRP3 inhibitors and provide a promising foundation for developing therapies targeting NLRP3-driven inflammatory diseases.
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BibTeX
@article{woo2026pharmacological,
title = {{Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation}},
author = {Hawon Woo and Yeonseo Jang and Soyeon Kim and Wonyoung Kim and Fenfen Zhang and Raghvendra Mall and Chirag N Patel and Melan Kurera and Chinh Ngo and Simon H Jiang and Asia Nicotra and Bénédicte F Py and Min Zheng and Si Ming Man and Rajendra Karki},
journal = {EMBO Molecular Medicine},
year = {2026},
month = oct,
doi = {10.1038/s44321-026-00425-5},
url = {https://hal.science/hal-05774292v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation
AU - Hawon Woo
AU - Yeonseo Jang
AU - Soyeon Kim
AU - Wonyoung Kim
AU - Fenfen Zhang
AU - Raghvendra Mall
AU - Chirag N Patel
AU - Melan Kurera
AU - Chinh Ngo
AU - Simon H Jiang
AU - Asia Nicotra
AU - Bénédicte F Py
AU - Min Zheng
AU - Si Ming Man
AU - Rajendra Karki
PY - 2026
DA - 2026/10/01
JO - EMBO Molecular Medicine
DO - 10.1038/s44321-026-00425-5
UR - https://hal.science/hal-05774292v1
AB - The NLRP3 inflammasome is a key driver in inflammatory, infectious, metabolic, and neurodegenerative diseases. Although the NLRP3 inhibitor CRID3 (also known as MCC950) exhibits potent activity, it cannot inhibit several hyperactive NLRP3 mutations associated with autoinflammatory syndromes and has not progressed clinically, underscoring the need for the development of new NLRP3 inhibitors. Through a high-throughput screening, we identified LOC14, an isothiazolinone-containing small molecule, as a selective NLRP3 inhibitor. Distinct from CRID3, which targets the NACHT domain, LOC14 binds to or near the LRR domain of NLRP3 and inhibits both CRID3-responsive and CRID3-non-responsive hyperactive or gain-of-function NLRP3 variants. Furthermore, we identified that the carbonyl oxygen of the isothiazol-3(2H)-one moiety is critical for inhibitory activity. In vivo, LOC14 exerted anti-inflammatory activity in mouse models of colitis, sepsis, and psoriasis, demonstrating broad physiological and therapeutic relevance. Our findings highlight isothiazolinone-containing compounds as selective NLRP3 inhibitors and provide a promising foundation for developing therapies targeting NLRP3-driven inflammatory diseases.
SN - 1757-4676
SN - 1757-4684
ER -