Wang Zuoyang, Shi Zhichao, Yang Shiqi, Niu Zizhou, Shu Kaifei, Chen Linbo, Zhi Cailian, Liu Funian, Huang Wenjun, Fan Tingting, Jiang Yuyang
The State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China.
ACS Med Chem Lett. 2024 Aug 22;15(9):1516-1525. doi: 10.1021/acsmedchemlett.4c00256. eCollection 2024 Sep 12.
In recent years, it has been proposed that c-mesenchymal-to-epithelial transition factor (c-Met) and histone deacetylase (HDAC) dual inhibition is a promising cancer treatment strategy. Herein, a series of c-Met/HDAC dual inhibitors were designed and synthesized given their synergistic anticancer effect in breast cancer cells. Compound exhibited excellent inhibitory activity against c-Met (IC = 28.92 nM) and HDAC (85.68%@1000 nM) and inhibited the proliferation of all three breast cancer cell lines. Moreover, a mechanism investigation demonstrated that could simultaneously induce cell cycle arrest in the G/G phase and cell apoptosis in MDA-MB-231 cells, which was endorsed by c-Met and HDAC pathway blockade. It could also suppress cell invasion. Our results suggest that developing promising c-Met/HDAC dual inhibitors is a novel strategy for breast cancer therapy.
近年来，有人提出c-间充质-上皮转化因子（c-Met）和组蛋白脱乙酰基酶（HDAC）双重抑制是一种很有前景的癌症治疗策略。鉴于其在乳腺癌细胞中的协同抗癌作用，本文设计并合成了一系列c-Met/HDAC双重抑制剂。化合物 对c-Met（IC = 28.92 nM）和HDAC（1000 nM时抑制率为85.68%）表现出优异的抑制活性，并抑制了所有三种乳腺癌细胞系的增殖。此外，机制研究表明， 可同时诱导MDA-MB-231细胞在G/G期发生细胞周期阻滞和细胞凋亡，这一结果得到了c-Met和HDAC信号通路阻断的支持。它还能抑制细胞侵袭。我们的结果表明，开发有前景的c-Met/HDAC双重抑制剂是乳腺癌治疗的一种新策略。
