Zhang Xiao-Song, Liu Jin-Zhan, Mei Ying-Ying, Zhang Meng, Sun Li-Wei
Xinxiang Central Hospital, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, China.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2466093. doi: 10.1080/14756366.2025.2466093. Epub 2025 Feb 20.
Lysine-specific demethylase 1 (LSD1) is abnormally overexpressed in various tumour tissues of patients and has been an attractive anticancer target. In this work, a potent LSD1 inhibitor (compound ) was designed and synthesised by the molecular hybridisation strategy. It displays the potent antiproliferative activity against HepG2, HEP3B, HUH6, and HUH7 cells with IC values of 0.93, 2.09, 1.43, and 4.37 μM, respectively. Furthermore, compound is a selective and reversible LSD1 inhibitor with an IC value of 0.18 μM and increases the methylation levels of H3K4me1/2. Molecular docking studies showed that it formed hydrogen bonds, hydrophilic interactions and hydrophobic interactions with residues of LSD1. Anticancer mechanisms demonstrated that it suppresses migration and epithelial-mesenchymal transition process in HepG2 cells. Importantly, it exhibits potent anti-liver cancer effects without obvious toxic effects. These interesting findings suggested that compound , a novel LSD1 inhibitor, may be a promising therapeutic agent to treat liver cancer.
赖氨酸特异性去甲基化酶1（LSD1）在患者的各种肿瘤组织中异常过表达，一直是一个有吸引力的抗癌靶点。在这项工作中，通过分子杂交策略设计并合成了一种有效的LSD1抑制剂（化合物 ）。它对HepG2、HEP3B、HUH6和HUH7细胞显示出强大的抗增殖活性，IC值分别为0.93、2.09、1.43和4.37μM。此外，化合物 是一种选择性且可逆的LSD1抑制剂，IC值为0.18μM，可提高H3K4me1/2的甲基化水平。分子对接研究表明，它与LSD1的残基形成了氢键、亲水相互作用和疏水相互作用。抗癌机制表明，它抑制HepG2细胞的迁移和上皮-间质转化过程。重要的是，它表现出强大的抗肝癌作用且无明显毒性作用。这些有趣的发现表明，新型LSD1抑制剂化合物 可能是一种有前途的治疗肝癌的药物。
