基于三氮唑-二硫代氨基甲酸盐的赖氨酸特异性去甲基化酶 1（LSD1）选择性抑制剂抑制胃癌细胞生长、侵袭和迁移。
Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration.
机构信息
School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Departments of Urology, Pharmacology and Pharmaceutical Sciences, University of California, Irvine, Orange, USA.
出版信息
J Med Chem. 2013 Nov 14;56(21):8543-60. doi: 10.1021/jm401002r. Epub 2013 Nov 1.
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's expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole-dithiocarbamate 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.
赖氨酸特异性脱甲基酶 1（LSD1）是第一个被鉴定的组蛋白去甲基酶，在基因激活和抑制的表观遗传调控中发挥着重要作用。已有报道称，LSD1 的表达在几种恶性肿瘤中上调。在本研究中，我们设计并合成了五组 1,2,3-三唑-二硫代氨基甲酸酯杂合体，并筛选了它们对 LSD1 的抑制活性。我们发现，其中一些化合物，特别是化合物 26，对 LSD1 表现出最特异和最强的抑制作用。有趣的是，与 2-PCPA 相比，化合物 26 对 LSD1 过表达的胃癌细胞系 MGC-803 和 HGC-27 也表现出强大的选择性细胞毒性，以及显著抑制细胞迁移和侵袭。此外，化合物 26 还能有效抑制体内人胃癌细胞的肿瘤生长，且无不良反应迹象。这些发现表明，化合物 26 值得进一步研究，作为治疗 LSD1 过表达胃癌的先导化合物。
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