Discovery of a Dual-Target Inhibitor of CDK7 and HDAC1 That Induces Apoptosis and Inhibits Migration in Colorectal Cancer**

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2023-10-11 DOI:10.1002/cmdc.202300281

Yao Chen, Shuangqian Zhang, Zhijia Li, Bo Yin, Yi Liu, Prof. Dr. Lan Zhang

引用次数: 0

Abstract

Aberrant expression or dysfunction of cyclin-dependent kinase 7(CDK7) and histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.

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发现了一种CDK7和HDAC1的双重靶向抑制剂，该抑制剂诱导癌症细胞凋亡并抑制迁移。

细胞周期蛋白依赖性激酶7（CDK7）和组蛋白脱乙酰酶1（HDAC1）的异常表达或功能障碍与各种癌症的发生和发展有关。在本研究中，我们通过设计和合成包含THZ2和SAHA药效团的化合物，开发了一系列双靶点抑制剂。最有效的双靶抑制剂对几种类型的癌症细胞显示出强大的抑制活性，并对CDK7和HDAC1表现出有希望的抑制作用。经过进一步的机制研究，发现该抑制剂有效地将HCT-116细胞阻滞在G2期并诱导细胞凋亡。此外，它还显著阻碍了HCT-116细胞的迁移，并表现出显著的抗肿瘤作用。这些发现为CDK7和HDAC1的双靶向抑制剂的开发提供了强有力的支持，并为未来的癌症治疗提供了一条有前景的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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