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
  • 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: [email protected].
  • 6. Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, China; Shenzhen Winkey Technology Co., Ltd., Shenzhen 518000, China. Electronic address: [email protected].
  • 7. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: [email protected].
  • 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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