title: APC0576, a novel inhibitor of NF-kappaB-dependent gene activation, prevents pro-inflammatory cytokine-induced chemokine production in human endothelial cells.
abstract: Endothelial cells participate in the inflammatory and immune reactions. Endothelial cell activation is a recurrent phenomenon linked to the pathogenesis of diverse human diseases, such as acute and chronic inflammation and cardiovascular disorders. Pro-inflammatory cytokines (e.g., IL-1, TNF) are well-known activators of endothelial cells, since they strongly induce production of chemokines (e.g., IL-8, MCP-1) and cell adhesion molecules, resulting in an activation of inflammatory transcription factors such as NF-kappaB. We have established a cell-based reporter assay for the NF-kappaB-dependent gene activation in HUVEC. Using this assay system, we have identified a novel synthetic small molecule, APC0576, 5-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine, as an inhibitor of IL-1-induced NF-kappaB-dependent gene activation without any adverse effects on the cell viability. APC0576 represses the IL-1-induced release of chemokines (e.g., IL-8, MCP-1) in HUVEC. This inhibitory effect occurred at the level of mRNA expression. Despite having a strong inhibitory effect on the NF-kappaB-dependent transcriptional activation, APC0576 does not inhibit the IL-1-induced DNA binding of NF-kappaB, degradation of I-kappaB-alpha, or phosphorylation of RelA (p65). Although its molecular mechanism of action is not yet clear, APC0576 is a promising therapeutic candidate for diverse diseases involved in the pathogenic endothelial activation.
authors.affiliation: Discovery Research Laboratories, Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan. kenji_takehana@ajinomoto.com
authors.forename: Kenji
authors.initials: K
authors.lastname: Takehana
authors.forename: Atsushi
authors.initials: A
authors.lastname: Konishi
authors.forename: Akiko
authors.initials: A
authors.lastname: Oonuki
authors.forename: Misato
authors.initials: M
authors.lastname: Noguchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Yukio
authors.initials: Y
authors.lastname: Iino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051996:Transcription Factor RelA; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C457774:5-((2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-((2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine; D018925:Chemokines; D003521:Cyclopropanes; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011725:Pyridines; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha