Journal article
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
RC Coll, AAB Robertson, JJ Chae, SC Higgins, R Muñoz-Planillo, MC Inserra, I Vetter, LS Dungan, BG Monks, A Stutz, DE Croker, MS Butler, M Haneklaus, CE Sutton, G Núñez, E Latz, DL Kastner, KHG Mills, SL Masters, K Schroder Show all
Nature Medicine | Published : 2015
DOI: 10.1038/nm.3806
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 a..
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Awarded by Trinity College Dublin
Funding Acknowledgements
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).