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

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.