2. Academic Validation
  3. Discovery of a novel CDK4/6 and HDAC dual-targeting agent for the treatment of hepatocellular carcinoma

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

  • Bioorg Chem. 2025 Jan:154:108080. doi: 10.1016/j.bioorg.2024.108080.
Zizhou Niu 1,  Zhichao Shi 2,  Guoxiang Wu 1,  Yanping Liu 3,  Weibin Xie 4,  Fakai Liu 1,  Tingting Fan 2,  Kaifei Shu 1,  Qiuhua Huang 1,  Mengmeng Dai 3,  Cailian Zhi 2,  Cheng Qiu 3,  Yilin Li 4,  Lihong Wu 3,  Funian Liu 2,  Yijie Zhang 4,  Tingbiao Wu 2,  Yan Chen 5,  Zijian Liu 6,  Yue Hao 7,  Yuyang Jiang 8
Affiliations

Affiliations

  • 1 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.
  • 2 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
  • 3 The State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
  • 4 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 5 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: chenyan@szu.edu.cn.
  • 6 Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, China; Shenzhen Winkey Technology Co., Ltd., Shenzhen 518000, China. Electronic address: liuzijian1115@163.com.
  • 7 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: yuehao@szu.edu.cn.
  • 8 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; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
PMID: 39732089 DOI: 10.1016/j.bioorg.2024.108080
Abstract

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.

Keywords

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

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