A novel small-molecule inhibitor of NF-kappaB signaling

• Published in: Biochemical and biophysical research communications 2008-04, Vol.368 (4), p.1007-1013
• Main Authors: Nakajima, Hiroto, Fujiwara, Hideyasu, Furuichi, Yasuhiro, Tanaka, Keiji, Shimbara, Naoki
• Format: Article
• Language: English
• Subjects: Benzoates - pharmacology; Fluorescence Resonance Energy Transfer; I-kappa B Proteins - antagonists & inhibitors; NF-kappa B - antagonists & inhibitors; NF-KappaB Inhibitor alpha; Pyrazoles - pharmacology; Reproducibility of Results; Signal Transduction - drug effects; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1090-2104
• DOI: 10.1016/j.bbrc.2008.01.166

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.