2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Quinoline-Based Hydroxamic Acid Derivatives as Dual DNMT and HDAC Inhibitors with Potent Anti-Breast Cancer Activity

Design, Synthesis, and Biological Evaluation of Quinoline-Based Hydroxamic Acid Derivatives as Dual DNMT and HDAC Inhibitors with Potent Anti-Breast Cancer Activity

  • J Med Chem. 2025 Sep 25;68(18):19022-19040. doi: 10.1021/acs.jmedchem.5c01092.
Huaxin Lin 1 2,  Wenwen Zheng 1,  Zigao Yuan 3,  Lulu Li 3,  Yuling Tan 1,  Wenjun Huang 1,  Jiaqi Liu 4,  Zixuan Qiu 4,  Qinyuan Li 3,  Bizhu Chu 1,  Yuyang Jiang 1 3 4 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
  • 2 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
  • 3 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China.
  • 4 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 5 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
PMID: 40878672 DOI: 10.1021/acs.jmedchem.5c01092
Abstract

Both DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) play complementary roles in epigenetic regulation, and their simultaneous inhibition is a promising strategy for Cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of quinoline-based hydroxamic acid derivatives as dual DNMT and HDAC inhibitors. Notably, compound Y7 emerged as the most potent dual-target inhibitor, with IC50 values of 365 and 0.20 nM against DNMT1 and HDAC1, respectively. Furthermore, Y7 exhibited significantly enhanced antitumor efficacy compared with that of decitabine-SAHA combination in breast Cancer cells. The results of in vivo experiments showed that Y7 markedly reduced tumor growth in both xenograft and transgenic breast Cancer mouse models, presenting superior efficacy than the decitabine-SAHA combination without detectable toxicity. Altogether, these results present Y7 as a promising dual DNMT and HDAC Inhibitor with the potential for further development as a therapeutic agent for breast Cancer.

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