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

Zizhou Niu; Zhichao Shi; Guoxiang Wu; Yanping Liu; Weibin Xie; Fakai Liu; Tingting Fan; Kaifei Shu; Qiuhua Huang; Mengmeng Dai; Cailian Zhi; Cheng Qiu; Yilin Li; Lihong Wu; Funian Liu; Yijie Zhang; Tingbiao Wu; Yan Chen; Zijian Liu; Yue Hao; Yuyang Jiang

doi:10.1016/j.bioorg.2024.108080

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

Bioorg Chem. 2024 Dec 20:154:108080. doi: 10.1016/j.bioorg.2024.108080. Online ahead of print.

Authors

Zizhou Niu¹, Zhichao Shi², Guoxiang Wu¹, Yanping Liu³, Weibin Xie⁴, Fakai Liu¹, Tingting Fan², Kaifei Shu¹, Qiuhua Huang¹, Mengmeng Dai³, Cailian Zhi², Cheng Qiu³, Yilin Li⁴, Lihong Wu³, Funian Liu², Yijie Zhang⁴, Tingbiao Wu², Yan Chen⁵, Zijian Liu⁶, Yue Hao⁷, Yuyang Jiang⁸

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.