Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang, China.
Arch Pharm (Weinheim). 2021 Aug;354(8):e2100102. doi: 10.1002/ardp.202100102. Epub 2021 May 13.
The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1 inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1-B5, and C4 showed preferable inhibitory effects on LSD1, with IC = 0.19-0.82 µM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.
赖氨酸特异性组蛋白去甲基化酶 1（LSD1）的异常表达与不同类型的癌症相关，LSD1 的抑制活性似乎在癌症治疗中有很高的治疗潜力。在这里，我们报告了新型 5-氨基四氢喹啉基 LSD1 抑制剂的设计、合成和生化评估。其中，化合物 A6、A8、B1-B5 和 C4 对 LSD1 表现出较好的抑制作用，IC = 0.19-0.82 μM。选择了几种有效的化合物来评估它们对 LSD1 高表达的 A549 细胞和 MCF-7 细胞的增殖活性。通过分子对接揭示了化合物的潜在结合模式，以合理化化合物对 LSD1 的活性。我们的数据表明，5-氨基四氢喹啉骨架可以作为开发用于癌症治疗的有效 LSD1 抑制剂的起点。
