2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel HDAC/CD13 dual inhibitors for the treatment of cancer

Design, synthesis, and biological evaluation of novel HDAC/CD13 dual inhibitors for the treatment of cancer

  • Eur J Med Chem. 2023 Nov 15;260:115752. doi: 10.1016/j.ejmech.2023.115752.
Geng Jia 1,  Kangjing Qi 1,  Baogeng Hou 1,  Kairui Yue 1,  Tongqiang Xu 2,  Yuqi Jiang 3,  Xiaoyang Li 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • 2 Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong, 266071, PR China.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong, 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong, 266071, PR China. Electronic address: jiangyuqi@ouc.edu.cn.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong, 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong, 266071, PR China. Electronic address: lixiaoyang@ouc.edu.cn.
PMID: 37647727 DOI: 10.1016/j.ejmech.2023.115752
Abstract

Aminopeptidase N (APN/CD13) plays a role in tumors progression, but its inhibitor lacks cytotoxicity and is used as an adjuvant drug in Cancer treatment. Histone deacetylases (HDACs) are a type of epigenetic targets, and HDAC inhibitors are cytotoxic and exhibit synergistic effects with other Anticancer agents. Herein, a novel series of HDAC/CD13 dual inhibitors were rationally designed and synthesized to combine the anti-metastasis and anti-invasion of CD13 Inhibitor with the cytotoxic of HDAC Inhibitor. The representative compound 12 exhibited more potent inhibitory activity against human CD13, HDAC1-3, and antiproliferative activity than positive controls bestatin and SAHA. Compound 12 effectively induced Apoptosis in MV4-11 cells, while arresting A549 cells in G2/M phase. Moreover, 12 exhibited significantly better anti-metastasis and anti-invasion effects than mono-inhibitors 32 and 38, indicating that it is a promising anti-cancer agent for further investigation.

Keywords

CD13 inhibitor; Cancer; Dual inhibitor; HDAC inhibitor; Rational drug design.

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