A novel small-molecule inhibitor of NF-{kappa}B signaling

Journal Article · Fri Apr 18 04:00:00 EDT 2008 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2008.01.166· OSTI ID:21043716

Nakajima, Hiroto; Fujiwara, Hideyasu ^[1]; Furuichi, Yasuhiro ^[1]; Tanaka, Keiji ^[2]; Shimbara, Naoki ^[1]

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1. Department of Drug Discovery Research, GENECARE Research Institute, 19-2 Kajiwara, Kamakura, Kanagawa 247-0063 (Japan)
2. Tokyo Metropolitan Institute of Medical Science, Laboratory of Frontier Science, 18-22 Honkomagome 3-chome, Bunkyko-ku, Tokyo 113-8613 (Japan)

The inducible transcription factor NF-{kappa}B regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-{kappa}B signaling are potentially useful for treatment of inflammation and cancer. NF-{kappa}B is canonically activated by preferential disposal of its inhibitory protein; I{kappa}B, which suppresses the nuclear translocation of NF-{kappa}B. I{kappa}B{alpha} (a major member of I{kappa}B family proteins) is phosphorylated with an I{kappa}B kinase (IKK) and subsequently polyubiquitylated by SCF{sup {beta}}{sup TrCP1} ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed I{kappa}B{alpha} ubiquitylation, but not I{kappa}B{alpha} phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of I{kappa}B{alpha} stimulated by TNF{alpha} and a set of downstream responses coupled to NF-{kappa}B 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-{kappa}B signaling.

• OSTI ID: 21043716
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 368; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

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