Triazole鈥揇ithiocarbamate Based Selective Lysine Specific Demethylase 1 (LSD1) Inactivators Inhibit Gastric Cancer Cell Growth, Invasion, and Migration

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• 作者：Yi-Chao Zheng ; Ying-Chao Duan ; Jin-Lian Ma ; Rui-Min Xu ; Xiaolin Zi ; Wen-Lei Lv ; Meng-Meng Wang ; Xian-Wei Ye ; Shun Zhu ; David Mobley ; Yan-Yan Zhu ; Jun-Wei Wang ; Jin-Feng Li ; Zhi-Ru Wang ; Wen Zhao ; Hong-Min Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8543-8560
• 全文大小：1051K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1鈥檚 expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole鈥揹ithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.