title: A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.
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.
authors: 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.
authors: Rebecca C
authors: RC
authors: Coll
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors: Avril A B
authors: AA
authors: Robertson
authors: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Jae Jin
authors: JJ
authors: Chae
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Sarah C
authors: SC
authors: Higgins
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Raúl
authors: R
authors: Muñoz-Planillo
authors: 1] Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. [2] School of Pharmacy, University of Queensland, Brisbane, Australia.
authors: Marco C
authors: MC
authors: Inserra
authors: 1] Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. [2] School of Pharmacy, University of Queensland, Brisbane, Australia.
authors: Irina
authors: I
authors: Vetter
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Lara S
authors: LS
authors: Dungan
authors: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
authors: Brian G
authors: BG
authors: Monks
authors: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
authors: Andrea
authors: A
authors: Stutz
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors: Daniel E
authors: DE
authors: Croker
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors: Mark S
authors: MS
authors: Butler
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Moritz
authors: M
authors: Haneklaus
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Caroline E
authors: CE
authors: Sutton
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Gabriel
authors: G
authors: Núñez
authors: 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.
authors: Eicke
authors: E
authors: Latz
authors: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Daniel L
authors: DL
authors: Kastner
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Kingston H G
authors: KH
authors: Mills
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors: Seth L
authors: 000000034763576X
authors: SL
authors: Masters
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors: Kate
authors: K
authors: Schroder
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors: Matthew A
authors: MA
authors: Cooper
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Luke A J
authors: LA
authors: O'Neill
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000188:drug therapy*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007192:Indenes; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D007249:Inflammation; D053583:Interleukin-1beta / Q000187:drug effects*; D051379:Mice; D009103:Multiple Sclerosis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013449:Sulfonamides; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002352:Carrier Proteins; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; C587672:IL1B protein, mouse; D007192:Indenes; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D013449:Sulfonamides; D013450:Sulfones; C000597426:N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide