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Nat Med. 2015 Mar;21(3):248-55. doi: 10.1038/nm.3806. Epub 2015 Feb 16.

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

Author information

1
1] School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. [2] Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
2
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
3
Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
4
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
5
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
6
1] Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. [2] School of Pharmacy, University of Queensland, Brisbane, Australia.
7
Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
8
1] Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany. [2] Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [3] German Center for Neurodegenerative Diseases, Bonn, Germany.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Abstract

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

PMID:
25686105
PMCID:
PMC4392179
DOI:
10.1038/nm.3806
[Indexed for MEDLINE]
Free PMC Article

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