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

Rebecca C Coll, Avril A B Robertson, Jae Jin Chae, Sarah C Higgins, Raúl Muñoz-Planillo, Marco C Inserra, Irina Vetter, Lara S Dungan, Brian G Monks, Andrea Stutz, Daniel E Croker, Mark S Butler, Moritz Haneklaus, Caroline E Sutton, Gabriel Núñez, Eicke Latz, Daniel L Kastner, Kingston H G Mills, Seth L Masters, Kate SchroderMatthew A Cooper, Luke A J O'Neill

Research output: Contribution to journalArticle

874 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)248-55
Number of pages8
JournalNature Medicine
Volume21
Issue number3
DOIs
Publication statusPublished - Mar 2015
Externally publishedYes

Keywords

  • Animals
  • Carrier Proteins/antagonists & inhibitors
  • Cryopyrin-Associated Periodic Syndromes/drug therapy
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental/drug therapy
  • Heterocyclic Compounds, 4 or More Rings/pharmacology
  • Humans
  • Inflammasomes/antagonists & inhibitors
  • Inflammation
  • Interleukin-1beta/drug effects
  • Mice
  • Multiple Sclerosis
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Sulfones/pharmacology

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  • Cite this

    Coll, R. C., Robertson, A. A. B., Chae, J. J., Higgins, S. C., Muñoz-Planillo, R., Inserra, M. C., Vetter, I., Dungan, L. S., Monks, B. G., Stutz, A., Croker, D. E., Butler, M. S., Haneklaus, M., Sutton, C. E., Núñez, G., Latz, E., Kastner, D. L., Mills, K. H. G., Masters, S. L., ... O'Neill, L. A. J. (2015). A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine, 21(3), 248-55. https://doi.org/10.1038/nm.3806