| Literature DB >> 25686105 |
Rebecca C Coll1, Avril A B Robertson2, Jae Jin Chae3, Sarah C Higgins4, Raúl Muñoz-Planillo5, Marco C Inserra6, Irina Vetter6, Lara S Dungan4, Brian G Monks7, Andrea Stutz7, Daniel E Croker2, Mark S Butler2, Moritz Haneklaus4, Caroline E Sutton4, Gabriel Núñez5, Eicke Latz8, Daniel L Kastner3, Kingston H G Mills4, Seth L Masters9, Kate Schroder2, Matthew A Cooper2, Luke A J O'Neill4.
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.Entities:
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Year: 2015 PMID： 25686105 PMCID： PMC4392179 DOI： 10.1038/nm.3806
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440