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  • 标题:Inhibitory Effects of a New 1 H -Pyrrolo[3,2- c ]pyridine Derivative, KIST101029, on Activator Protein-1 Activity and Neoplastic Cell Transformation Induced by Insulin-Like Growth Factor-1
  • 本地全文:下载
  • 作者:Hyo Jeong Yun ; Garam Kim ; Prem Khanal
  • 期刊名称:Biological and Pharmaceutical Bulletin
  • 印刷版ISSN:0918-6158
  • 电子版ISSN:1347-5215
  • 出版年度:2013
  • 卷号:36
  • 期号:9
  • 页码:1466-1473
  • DOI:10.1248/bpb.b13-00244
  • 出版社:The Pharmaceutical Society of Japan
  • 摘要:

    Diarylureas and diarylamides derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of diarylurea and diarylamide derivatives, we synthesized a new series of diarylureas and diarylamides containing pyrrolo[3,2- c ]pyridine scaffold. In this study, we demonstrate that a N -(3-(4-benzamido-1 H -pyrrolo[3,2- c ]pyridin-1-yl)phenyl)-4-morpholino-3-(trifluoromethyl)benzamide, KIST101029, inhibits neoplastic cell transformation induced by insulin-like growth factor 1 (IGF-1) in mouse epidermal JB6 Cl41 cells. The KIST101029 compound inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK), c-jun N-terminal kinases (JNK), and mechanistic target of rapamycin (mTOR) signaling pathways induced by IGF-1 in JB6 Cl41 cells, resulting in the inhibition of c-fos and c-jun transcriptional activity. In addition, the KIST101029 inhibited the associated activator protein-1 (AP-1) transactivation activity and cell transformation induced by IGF-1 in JB6 Cl41 cells. Consistent with these observations, in vivo chorioallantoic membrane assay also showed that the KIST101029 inhibited IGF-1-induced tumorigenicity of JB6 Cl41 cells. Importantly, KIST101029 suppressed the colony formation of A375 cells in soft agar. Taken together, these results indicate that a KIST101029 might exert chemopreventive effects through the inhibition of phosphorylation of MAPK and mTOR signaling pathway.

  • 关键词:KIST101029; insulin-like growth factor 1; activator protein-1; cell transformation; c-Fos; c-Jun
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