新型NSD2和HDAC2双靶向抑制剂治疗肝癌:基于结构的虚拟筛选、分子动力学模拟和体内外生物活性评价

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xing Jin, Yuting Wang, Jing Chen, Miaomiao Niu, Yang Yang, Qiaoxuan Zhang, Guangyu Bao
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引用次数: 0

摘要

肝癌表现出高度的异质性,涉及复杂的机制。最近的研究揭示了组蛋白赖氨酸甲基化和乙酰化在肝癌发生的表观遗传调控中的重要作用。在这项研究中,使用基于结构的虚拟筛选方法鉴定了五种能够同时靶向组蛋白赖氨酸甲基转移酶核受体结合SET结构域2 (NSD2)和组蛋白去乙酰化酶2 (HDAC2)的抑制剂。DT-NH-1对NSD2 (IC50 = 0.08±0.03 μM)和HDAC2 (IC50 = 5.24±0.87 nM)具有明显的抑制作用。DT-NH-1对多种肝癌细胞系,特别是HepG2细胞具有较强的抗增殖活性,具有较高的生物安全性。在HepG2细胞的实验性异种移植模型中,DT-NH-1显示肿瘤生长明显减少。因此,这些发现表明,DT-NH-1将是一种有希望的先导化合物,用于治疗肝癌的表观遗传双靶点抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and in vitro and in vivo biological activity evaluations.

Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC50 = 0.08 ± 0.03 μM) and HDAC2 (IC50 = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.

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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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