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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We thank A. Kitanovic (German Center for Neurodegenerative Diseases) for image analysis (Fig. 3c), S. Corr (Trinity College Dublin) for providing S. typhimurium UK-1 strain and H.M. Hoffman (University of California, San Diego) for providing Nlrp3 (A350VneoR) mice. This work was supported by the following funding bodies, grants and fellowships. L.A.J.O'N. and R.C.C.: Science Foundation Ireland (G20598). D.L.K. and J.J.C.: Intramural Research Program of the National Human Genome Research Institute, US National Institutes of Health. S.C.H., C.E.S. and K.H.G.M.: Science Foundation Ireland (11/PI/1036) and (07/SRC/B1144). I.V.: Australian Research Council (FT130101215). G.N.: US National Institutes of Health (DK091191) and (DK095782). E.L.: German Research Foundation (SFB645, SFB670, SFB704, TRR57), European Research Council (ERC, InflammAct) and Excellence Cluster ImmunoSensation. S.L.M.: VESKI innovation fellowship and National Health and Medical Research Council of Australia (1032065) and (1057815). K.S.: Queensland Smart Futures Fund and Australian Research Council (FT130100361). L.A.J.O'N.: ERC Advanced Grant (E12435).
The authors declare no competing financial interests.
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Coll, R., Robertson, A., Chae, J. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21, 248–255 (2015). https://doi.org/10.1038/nm.3806
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