MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

Nat Chem Biol. 2019 Jun;15(6):556-559. doi: 10.1038/s41589-019-0277-7. Epub 2019 May 13.

Abstract

Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / antagonists & inhibitors*
  • Adenosine Triphosphate / metabolism
  • Binding Sites / drug effects
  • Furans
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Hydrolysis / drug effects
  • Indenes
  • Inflammasomes / antagonists & inhibitors*
  • Inflammasomes / biosynthesis
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Sulfonamides
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • Furans
  • Heterocyclic Compounds, 4 or More Rings
  • Indenes
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Sulfonamides
  • Sulfones
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
  • Adenosine Triphosphate