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A selective small-molecule nuclear factor-kappaB inhibitor from a high-throughput cell-based assay for "activator protein-1 hits".

Abstract
NSC 676914 has been identified as a selective nuclear factor-kappaB (NF-kappaB) inhibitor that does not inhibit cell proliferation. This compound was originally identified in a high-throughput cell-based assay for activator protein-1 (AP-1) inhibitors using synthetic compound libraries and the National Cancer Institute natural product repository. NSC 676914 shows activity against NF-kappaB in luciferase reporter assays at concentrations much less than the IC50 for AP-1. A serum response element reporter used as a specificity control and indicator of cell proliferation was relatively insensitive to the compound. Pretreatment with NSC 676914 is here shown to repress 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IkappaB-alpha phosphorylation and translocation of p65/50 to the nucleus but not the processing of p52 from p100, suggesting the inhibition of NF-kappaB regulator IKKbeta rather than IKKalpha. Inhibition of NF-kappaB activation occurred as a consequence of blocking phosphorylation of IKK. Induction of IkappaB-alpha phosphorylation by TPA was diminished by pretreatment of NSC 676914 even at 1.1 mumol/L. In contrast, kinases c-Jun-NH2-kinase and extracellular signal-regulated kinases 1 and 2, important for AP-1 activation, showed no significant repression by this compound. Furthermore, a Matrigel invasion assay with breast cancer cell lines and a transformation assay in mouse JB6 cells revealed that TPA-induced invasion and transformation responses were completely repressed by this compound. These results suggest that NSC 676914 could be a novel inhibitor having potential therapeutic activity to target NF-kappaB for cancer treatment or prevention.
AuthorsMoon-Il Kang, Curtis J Henrich, Heidi R Bokesch, Kirk R Gustafson, James B McMahon, Alyson R Baker, Matthew R Young, Nancy H Colburn
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 3 Pg. 571-81 (Mar 2009) ISSN: 1535-7163 [Print] United States
PMID19258426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • 2-(4-((4-amino-2-methylphenyl)diazenyl)phenylsulfonyl)ethanesulfonoperoxoic acid
  • Antineoplastic Agents
  • Azo Compounds
  • I-kappa B Proteins
  • NF-kappa B
  • Small Molecule Libraries
  • Sulfonic Acids
  • Transcription Factor AP-1
Topics
  • Antineoplastic Agents (isolation & purification, pharmacology, therapeutic use)
  • Azo Compounds (pharmacology, therapeutic use)
  • Breast Neoplasms (drug therapy, genetics, pathology)
  • Cell Nucleus (drug effects, metabolism)
  • Cell Proliferation (drug effects)
  • Cells, Cultured
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • I-kappa B Proteins (metabolism)
  • Models, Biological
  • NF-kappa B (antagonists & inhibitors, genetics)
  • Phosphorylation (drug effects)
  • Small Molecule Libraries (analysis)
  • Substrate Specificity
  • Sulfonic Acids (pharmacology, therapeutic use)
  • Transcription Factor AP-1 (antagonists & inhibitors, genetics)
  • Transfection

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