title: 3-(13-Hydroxytridecyl)-1-[13-(3-pyridyl)tridecyl]pyridinium chloride (YM-53792), a novel inhibitor of NF-AT activation.
abstract: A compound, YM-53792, was identified as an inhibitor of interleukin-2 (IL-2) gene promoter activity, using a Jurkat cell-based reporter system in which the luciferase gene is regulated by the IL-2 gene promoter. Production of IL-2, interleukin-4 (IL-4) and interleukin-5 (IL-5) from human peripheral blood mononuclear cells was suppressed by YM-53792 in a dose-dependent fashion. Since expression of these cytokine genes is known to be regulated by NF-AT, we examined whether the promoter activity created by multimerization of NF-AT elements was inhibited with YM-53792. YM-53792 inhibited this promoter activity, but not AP-1- and NF-kappaB-driven promoter activities nor SV40 enhancer/promoter activity. In addition, electrophoretic mobility shift assays did not detect NF-AT/DNA complexes when nuclear extract prepared from YM-53792-treated, PMA/A23187-stimulated Jurkat cells was used, whereas AP-1/DNA complexes were observed. These results suggest that YM-53792 specifically inhibits the activation of NF-AT.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kuromitsu
authors.forename: M
authors.initials: M
authors.lastname: Fukunaga
authors.forename: A C
authors.initials: AC
authors.lastname: Lennard
authors.forename: Y
authors.initials: Y
authors.lastname: Masuho
authors.forename: S
authors.initials: S
authors.lastname: Nakada
mesh_terms: D016572:Cyclosporine / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D019169:Jurkat Cells; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011726:Pyridinium Compounds / Q000494:pharmacology*; D016559:Tacrolimus / Q000009:adverse effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011726:Pyridinium Compounds; D014157:Transcription Factors; C109147:YM 53792; D016572:Cyclosporine; D016559:Tacrolimus