MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel potential therapeutic for NLRP3 driven diseases — ASN Events
  1. Schedule
  2. Concurrent Mini-Symposium 1
  3. MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel potential therapeutic for NLRP3 driven diseases

MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel potential therapeutic for NLRP3 driven diseases (#30)

Rebecca C Coll 1 2 , Avril AB Robertson 1 , Jae Jin Chae 3 , Sarah C Higgins 2 , Lara S Dungan 2 , Raul Muñoz-Planillo 4 , Brian G Monks 5 , Daniel E Croker 1 , Caroline E Sutton 2 , Andrea Stutz 5 , Gabriel Nunez 4 , Eicke Latz 5 , Daniel L Kastner 3 , Kingston HG Mills 2 , Seth L Masters 6 , Kate Schroder 7 , Matt A Cooper 7 , Luke AJ O'Neill 2
  1. Institute for Molecular Bioscience , University of Queensland, St Lucia, QLD, Australia
  2. Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
  3. Inflammatory Disease Section, Medical Genetics Branch,, National Institutes of Health, National Human Genome Research Institute,, Bethesda, Maryland 20892, USA
  4. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
  5. Institute of Innate Immunity, University of Bonn, Bonn, Germany
  6. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  7. Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, University of Queensland, St Lucia, Queensland, Australia

Rebecca C. Coll and Avril A. B. Roberston will both present this work.

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. There is a compelling rationale to develop a potent, selective inhibitor of NLRP3. We demonstrate that a small molecule, MCC950, specifically blocks NLRP3 activation at nanomolar potency in response to numerous stimuli. MCC950 potently inhibits ASC oligomerisation, caspase-1 activation, IL-1β secretion and cell death in response to NLRP3 but not AIM2, NLRC4 or NLRP1 inflammasome activation. MCC950 can block IL-1b in vivo and attenuates the course of the NLRP3 dependent, IL-1b 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.