A small molecule inhibitior of the NLRP3 inflammasome is a potential therapeutic for inflammatory diseases

By Rebecca C. Coll, A. Robertson, J. Chae, Sarah C. Higgins, Raúl Muñoz-Planillo, Marco C. Inserra, I. Vetter, Lara S. Dungan, Brian G. Monks, A. Stutz and 12 more. Nature Medicine, 2015

2,420 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3c9a371904d109629d9b3a4df73aa10307e7c075

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In Immunology

1. M. Lamkanfi
2. V. Hornung
3. G. van Loo
4. D. Su
5. Kate Schroder
6. Liang Liu
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In Molecular Biology

1. Kate Schroder
2. M. Lamkanfi
3. V. Hornung
4. K. Walsh
5. G. van Loo
6. D. Su
7. Danyang Li
8. Wei Jiang

Citations in the corpus

• Human Monocytes Engage an Alternative Inflammasome Pathway. (2016, positive): “To this end, we made use of small-molecule inhibitors to target NLRP3 (MCC950) (Coll et al., 2015), caspase-1 (Z-YVAD-FMK), caspase-8 (Z-IETD-FMK), pan-caspases (Z-VAD-FMK), and RIPK3 (GSK872) (Figure S7G).”
• Inflammasomes in neuroinflammatory and neurodegenerative diseases (2019, background): “Moreover, the pharmacological NLRP3 inflammasome inhibitor MCC950/CRID3 was shown to suppress IL-1b production and attenuate EAE severity in wild-type mice (Coll et al, 2015).”
• NLRP3 inflammasome and its inhibitors: a review (2015, background): “Coll et al. (2015) discovered that MCC950, a diarylsulfonylurea-containing compound known to inhibit caspase-1-dependent processing of IL-1β (Perregaux et al., 2001), also inhibits both canonical and non-canonical activation of the NLRP3 inflammasome.”
• Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. (2016, background): “…(Wang et al., 2015d), DPP-4 inhibitors (Dai et al., 2014), ellagic acid (Tang et al., 2015), isoliquiritigenin (Honda et al., 2014), MCC950 (Coll et al., 2015), and chrysophanol (Zhang et al., 2014) has been shown to provide significant protective effects against inflammatory diseases.”