Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine

Nat Commun. 2015 Mar 27;6:6522. doi: 10.1038/ncomms7522.

Abstract

Aberrant activation of NF-κB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-κB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-κB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKα/β and suppresses their activities through an allosteric effect, leading to the inhibition of both canonical and non-canonical NF-κB pathways. Remarkably, ainsliadimer A induces cell death of various cancer cells and represses in vivo tumour growth and endotoxin-mediated inflammatory responses. Ainsliadimer A is thus a natural product targeting the cysteine 46 of IKKα/β to block NF-κB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Conserved Sequence
  • Cysteine / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / drug effects*
  • I-kappa B Kinase / metabolism
  • Lactones / metabolism
  • Lactones / pharmacology*
  • Mice
  • NF-kappa B / drug effects*
  • NF-kappa B / metabolism
  • Neoplasms / metabolism*
  • RAW 264.7 Cells
  • Sesquiterpenes / metabolism
  • Sesquiterpenes / pharmacology*
  • Signal Transduction / drug effects*

Substances

  • Lactones
  • NF-kappa B
  • Sesquiterpenes
  • ainsliadimer A
  • I-kappa B Kinase
  • Cysteine