Science Bite (3 min Oral Presentation) Lorne Infection and Immunity 2019

Mechanism of action of the small-molecule NLRP3 inflammasome inhibitor MCC950 (#58)

Rebecca C Coll 1 , James R Hill 1 , Christopher J Day 2 , Alina Zamoshnikova 3 , Dave Boucher 1 , Nicholas L Massey 1 , Michael P Jennings 2 , Avril AB Robertson 1 4 , Kate Schroder 1
  1. Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, University of Queensland, St Lucia, Queensland, Australia
  2. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  3. The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
  4. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) is a cytosolic sensor for disrupted metabolic or cellular homeostasis. Upon activation, NLRP3 forms an inflammasome complex that drives the secretion of the pro-inflammatory cytokines IL-1β and IL-18, and triggers inflammatory cell death known as pyroptosis.

NLRP3-driven inflammation causes the rare inherited cryopyrin-associated periodic syndromes (CAPS), and is also pathological in the development of many prevalent diseases including Alzheimer’s, Parkinson’s, gout, atherosclerosis, non-alcoholic fatty liver disease, and asthma. Inhibitors of NLRP3 are thus potential treatments for many of these diseases with unmet clinical needs.

We previously described MCC950, a small-molecule that blocks NLRP3 inflammasome activation. MCC950 is an effective inhibitor of NLRP3-driven inflammation in vivo, and has been validated in many different disease models and species. Given the translational potential of NLRP3 inhibition, and the importance of understanding mechanism of action in de-risking drug development, we endeavoured to define the molecular target of MCC950.

In this study we use methods including drug affinity responsive target stability (DARTS) assays, immunoprecipitation assays, surface plasmon resonance analysis, and a photo-affinity labelling strategy, to identify the molecular target of MCC950. Our data reveal the mechanism of action of MCC950, the most potent and specific NLRP3 inhibitor described to date, and provide a basis for further rational development of small-molecule inhibitors to treat NLRP3-driven inflammatory diseases.