Discovery of a novel CDK4/6 and HDAC dual-targeting agent for the treatment of hepatocellular carcinoma

被引：3

作者：

Niu, Zizhou ^{[1
,2
]}

Shi, Zhichao ^{[2
]}

Wu, Guoxiang ^{[1
,2
]}

Liu, Yanping ^{[1
]}

Xie, Weibin ^{[3
]}

Liu, Fakai ^{[1
,2
]}

Fan, Tingting ^{[2
]}

Shu, Kaifei ^{[1
,2
]}

Huang, Qiuhua ^{[1
,2
]}

Dai, Mengmeng ^{[1
]}

Zhi, Cailian ^{[2
]}

Qiu, Cheng ^{[1
]}

Li, Yilin ^{[3
]}

Wu, Lihong ^{[1
]}

Liu, Funian ^{[2
]}

Zhang, Yijie ^{[3
]}

Wu, Tingbiao ^{[2
]}

Chen, Yan ^{[3
]}

Liu, Zijian ^{[4
,5
]}

Hao, Yue ^{[3
]}

Jiang, Yuyang ^{[1
,2
,6
]}

机构：

[1] Tsinghua Univ, Tsinghua Shenzhen Int Grad Sch, State Key Lab Chem Oncogen, Shenzhen 518055, Peoples R China

[2] Shenzhen Bay Lab, Inst Biomed Hlth Technol & Engn, Shenzhen 518132, Peoples R China

[3] Shenzhen Univ, Med Sch, Sch Pharm, Shenzhen 518055, Peoples R China

[4] Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen 518057, Peoples R China

[5] Shenzhen Winkey Technol Co Ltd, Shenzhen 518000, Peoples R China

[6] Tsinghua Univ, Sch Pharmaceut Sci, Beijing 100084, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2025年 / 154卷

关键词：

Hepatocellular carcinoma; Cyclin-dependent kinase; Histone deacetylase; Dual-targeting inhibitors; Antitumor; CANCER; INHIBITORS;

D O I：

10.1016/j.bioorg.2024.108080

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The down-regulation of p21 after long-term CDK4/6 inhibition represents a key mechanism causing resistance to CDK4/6 inhibitors in some tumor cells, while the HDAC inhibitor could upregulate the level of p21. Herein, a series of novel CDK4/6 and HDAC dual-targeting inhibitors based on the moiety of palbociclib were designed and synthesized. Among them, compound N14 potently inhibited CDK4/6 and HDAC1/6 at nanomolar levels and induced cell apoptosis and G0/G1 phase arrest through HDAC-p21-CDK signaling pathway in HuH-7 cell line. And N14 also upregulated the expression of acetyl-H3 and p21. Furthermore, N14 significantly suppresses the proliferation of various HCC cells and the HuH-7 xenograft model without evident toxicity. Our study suggests compound N14 is a novel dual-targeting CDK4/6-HDAC inhibitor that represents a promising treatment strategy for HCC.

引用

页数：12

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