Studies on gambogic acid (IV): Exploring structure-activity relationship with IκB kinase-beta (IKKβ)

Eur J Med Chem. 2012 May:51:110-23. doi: 10.1016/j.ejmech.2012.02.029. Epub 2012 Mar 3.


Previously we have reported a series of gambogic acid's analogs and have identified a compound that possessed comparable in vitro growth inhibitory effect as gambogic acid. However, their target protein as well as the key pharmacophoric motifs on the target have not been identified yet. Herein we report that gambogic acid and its analogs inhibit the activity of IκB Kinase-beta (IKKβ) through suppressing the activation of TNFα/NF-κB pathway, which in turn induces A549 and U251 cell apoptosis. IKKβ can serve as one of gambogic acid's targets. The preparation of the compounds was carefully discussed in the article. Caged 4-oxa-tricyclo[,7)]dec-2-one xanthone, which was identified as the pharmacophoric scaffold, represents a promising therapeutic agent for cancer and useful probe against NF-κB pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / chemistry
  • Models, Molecular
  • NF-kappa B / metabolism
  • Protein Conformation
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / metabolism
  • Xanthones / chemistry*
  • Xanthones / pharmacology*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Xanthones
  • gambogic acid
  • I-kappa B Kinase