title: A novel small-molecule inhibitor of NF-kappaB signaling.
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.
authors.affiliation: Department of Drug Discovery Research, GENECARE Research Institute, 19-2 Kajiwara, Kamakura, Kanagawa 247-0063, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Nakajima
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Furuichi
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimbara
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C527646:4-(3-benzyl-4-(5-(2-fluorophenyl)-ruan-2-ylmethylene)-5-oxo-4,5-dihydropyrazol-1-yl)benzoic acid; D001565:Benzoates; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011720:Pyrazoles; D000072000:NF-KappaB Inhibitor alpha; D044767:Ubiquitin-Protein Ligases