A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-29 DOI:10.1016/j.bmc.2025.118178

Mingyang Liu , Muyan Ke , Hongchen Lu , Ziyu Feng , Kaixuan Wang , Danyang Wang , Kun Wang , Yueping Bai , Song Yang , Lu Miao , Qiang Chen , Mingming Sun , Changliang Shan , Jiancheng Hu , Lingyu Jiang , Hongzhen Jin , Jinfang Hu , Changjiang Huang , Rui Wang , Wei Zhao , Fan Yu

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Abstract

The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth in vitro and in vivo. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound 15a effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound 15a inhibited the proliferation and migration of HepG2 cells, and induced apoptosis in vitro. Furthermore, compound 15a significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound 15a enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.

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一种新的肉桂酸衍生物通过降解METTL16蛋白治疗肝癌

RNA甲基转移酶甲基转移酶样蛋白16 （methyltransferase - like protein 16, METTL16）在很大比例的肝细胞癌（HCC）中上调，其高表达与较差的临床结果相关。METTL16缺失在体外和体内抑制HCC生长。参考肉桂酸的结构，我们设计并合成了一系列新颖的小分子化合物，通过生物活性筛选发现化合物15a可有效降低METTL16水平，调节致癌PI3K/AKT通路信号。化合物15a在体外抑制HepG2细胞的增殖和迁移，诱导细胞凋亡。此外，化合物15a显著抑制裸鼠患者来源的肝癌异种移植物的生长，其效果优于多激酶抑制剂lenvatinib。化合物15a具有良好的疗效和生物安全性，使我们能够进一步开发该化合物用于临床治疗HCC和其他可能的癌症。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.