MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel therapeutic for NLRP3 driven diseases — ASN Events
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  3. MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel therapeutic for NLRP3 driven diseases

MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel therapeutic for NLRP3 driven diseases (#237)

Rebecca C Coll 1 , Avril AB Robertson 2 , Jae J Chae 3 , Sarah C Higgins 1 , Lara S Dungan 1 , Brian G Monks 4 , Eicke Latz 4 , Kingston G Mills 1 , Seth L Masters 5 , Matthew A Cooper 2 , Luke AJ O'Neill 1
  1. School of Biochemistry &Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Dublin 2, Ireland
  2. University of Queensland, St Lucia, QLD, Australia
  3. Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America
  4. Institute of Innate Immunity, University Hospitals, Biomedical Centre, University of Bonn Bonn, Germany
  5. The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia

NLRP3 is a critical component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes and complex diseases such as multiple sclerosis, type II diabetes and atherosclerosis. We demonstrate that a small molecule, MCC950, specifically blocks NLRP3 activation in response to numerous stimuli. MCC950 potently inhibits ASC oligomerisation, caspase-1 activation and IL-1ß secretion in response to NLRP3 but not AIM2, NLRC4 or NLRP1 inflammasome activation. MCC950 can block IL-1ß in vivo and attenuates the course of the NLRP3 dependent, IL-1ß driven disease model of multiple sclerosis, experimental autoimmune encephalomyelitis. Furthermore, MCC950 treatment rescues neonatal lethality in a murine model of cryopyrin associated periodic syndromes and is active in ex vivo samples from patients with Muckle-Wells syndrome. MCC950 is thus a novel potential therapeutic for NLRP3 associated syndromes and a useful tool for the further study of NLRP3 in human health and disease.