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Publications

Journal Article Ahead of print

PubMed: 41998138 DOI: 10.1038/s44321-026-00425-5

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

EMBO Mol Med

Authors: Hawon Woo, Yeonseo Jang, Soyeon Kim, Wonyoung Kim, Fenfen Zhang, Raghvendra Mall, Chirag N Patel, Melan Kurera, Chinh Ngo, Simon H Jiang, Asia Nicotra, Bénédicte F Py, Min Zheng, Si Ming Man, Rajendra Karki

Affiliations

  • Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
  • Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, China.
  • Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
  • Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
  • Division of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France.
  • Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, China.
  • Division of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
  • The Institute of Molecular Biology and Genetics (IMBG), Seoul National University, Seoul, Republic of Korea.

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.

MeSH

Therapeutics