Direct Rel/NF-κB inhibitors: structural basis for mechanism of action

Future Med Chem. 2009 Dec;1(9):1683-707. doi: 10.4155/fmc.09.96.


The Rel/NF-κB transcription factors have emerged as novel therapeutic targets for a variety of human diseases and pathological conditions, including inflammation, autoimmune diseases, cancer, ischemic injury, osteoporosis, transplant rejection and neurodegeneration. Several US FDA-approved drugs may, in part, attribute their therapeutic effects to the inhibition of the Rel/NF-κB pathway. Strategies for blocking the Rel/NF-κB signaling pathway have inspired the pharmaceutical industry to develop inhibitors for I-κB kinase, however, this article focuses instead on identifying natural compounds that directly target and inhibit DNA binding and transcription activity of Rel/NF-κB. These include compounds containing a quinone core, an α,β unsaturated carbonyl and a benzene diamine. By investigating the mechanisms of action of existing natural inhibitors, novel strategies and synthetic approaches can be devised that will facilitate the development of novel and selective Rel/NF-κB inhibitors with better safety profiles.

Publication types

  • Review

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / metabolism
  • Ketones / chemistry
  • Ketones / therapeutic use
  • Mice
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Quinones / chemistry
  • Quinones / therapeutic use
  • Signal Transduction
  • Transcription Factor RelA / antagonists & inhibitors*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism


  • Ketones
  • NF-kappa B
  • Quinones
  • Transcription Factor RelA
  • I-kappa B Kinase