Discovery of a selective and reversible LSD1 inhibitor with potent anticancer effects in vitro and in vivo.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xiao-Song Zhang, Jin-Zhan Liu, Ying-Ying Mei, Meng Zhang, Li-Wei Sun
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引用次数: 0

Abstract

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 14) was designed and synthesised by the molecular hybridisation strategy. It displays the potent antiproliferative activity against HepG2, HEP3B, HUH6, and HUH7 cells with IC50 values of 0.93, 2.09, 1.43, and 4.37 μM, respectively. Furthermore, compound 14 is a selective and reversible LSD1 inhibitor with an IC50 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 in vivo without obvious toxic effects. These interesting findings suggested that compound 14, a novel LSD1 inhibitor, may be a promising therapeutic agent to treat liver cancer.

发现一种选择性和可逆性的LSD1抑制剂,在体外和体内具有有效的抗癌作用。
赖氨酸特异性去甲基酶1 (LSD1)在患者的各种肿瘤组织中异常过表达,是一种有吸引力的抗癌靶点。本研究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14)。对HepG2、HEP3B、HUH6和HUH7细胞具有较强的抗增殖活性,IC50值分别为0.93、2.09、1.43和4.37 μM。化合物14是选择性可逆的LSD1抑制剂,IC50值为0.18 μM,可提高h3k4me /2的甲基化水平。分子对接研究表明,它与LSD1残基形成氢键、亲水性和疏水性相互作用。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,它在体内表现出强大的抗肝癌作用,没有明显的毒性作用。这些有趣的发现表明,化合物14作为一种新型的LSD1抑制剂,可能是治疗肝癌的一种有前景的药物。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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