A novel small-molecule inhibitor of NF-kappaB signaling

Biochem Biophys Res Commun. 2008 Apr 18;368(4):1007-13. doi: 10.1016/j.bbrc.2008.01.166. Epub 2008 Feb 12.

Abstract

The inducible transcription factor NF-kappaB regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-kappaB signaling are potentially useful for treatment of inflammation and cancer. NF-kappaB is canonically activated by preferential disposal of its inhibitory protein; IkappaB, which suppresses the nuclear translocation of NF-kappaB. IkappaBalpha (a major member of IkappaB family proteins) is phosphorylated with an IkappaB kinase (IKK) and subsequently polyubiquitylated by SCF(betaTrCP1) ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed IkappaBalpha ubiquitylation, but not IkappaBalpha phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of IkappaBalpha stimulated by TNFalpha and a set of downstream responses coupled to NF-kappaB signaling but not those of p53 and beta-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-kappaB signaling.

MeSH terms

  • Benzoates / pharmacology*
  • Fluorescence Resonance Energy Transfer
  • I-kappa B Proteins / antagonists & inhibitors
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • Pyrazoles / pharmacology*
  • Reproducibility of Results
  • Signal Transduction / drug effects*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • 4-(3-benzyl-4-(5-(2-fluorophenyl)-ruan-2-ylmethylene)-5-oxo-4,5-dihydropyrazol-1-yl)benzoic acid
  • Benzoates
  • I-kappa B Proteins
  • NF-kappa B
  • Pyrazoles
  • NF-KappaB Inhibitor alpha
  • Ubiquitin-Protein Ligases