A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
A selective, small-molecule inhibitor of NLRP3 suppresses activation of the inflammasome in vitro and in vivo and attenuates inflammatory disease. The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant a...
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Published in | Nature medicine Vol. 21; no. 3; pp. 248 - 255 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.03.2015
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | A selective, small-molecule inhibitor of NLRP3 suppresses activation of the inflammasome
in vitro
and
in vivo
and attenuates inflammatory disease.
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-8956 1546-170X |
DOI: | 10.1038/nm.3806 |