发现新型曲奈普汀类衍生物作为治疗胃癌的 LSD1 抑制剂。
Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment.
机构信息
School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
Luohe Food Vocationl College, Luohe, 462333, China.
出版信息
Eur J Med Chem. 2023 May 5;251:115228. doi: 10.1016/j.ejmech.2023.115228. Epub 2023 Feb 23.
As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC values of 14.3, 22.8 and 16.3 μM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer.
作为一种重要的表观遗传调控因子，组蛋白赖氨酸特异性去甲基化酶 1（LSD1）已成为抗癌药物发现的一个有吸引力的靶点。在这项工作中，设计并合成了一系列反式环丙胺为基础的衍生物。其中，化合物 12u 对 LSD1 表现出最强的抑制活性（IC = 25.3 nM），并且对 MGC-803、KYSE450 和 HCT-116 细胞也表现出良好的增殖抑制作用，IC 值分别为 14.3、22.8 和 16.3 μM。进一步的研究表明，化合物 12u 可以直接作用于 LSD1，并在 MGC-803 细胞中抑制 LSD1，从而显著增加 H3K4 和 H3K9 的单/二甲基化水平。此外，化合物 12u 可以诱导 MGC-803 细胞凋亡和分化，抑制迁移和细胞干性。所有这些发现表明，化合物 12u 是一种有效的以反式环丙胺为基础的 LSD1 抑制剂，可抑制胃癌。
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