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 <b>Y7</b> emerged as the most potent dual-target inhibitor, with IC₅₀ values of 365 and 0.20 nM against DNMT1 and HDAC1, respectively. Furthermore, <b>Y7</b> exhibited significantly enhanced antitumor efficacy compared with that of decitabine-SAHA combination in breast cancer cells. The results of in vivo experiments showed that <b>Y7</b> 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 <b>Y7</b> as a promising dual DNMT and HDAC inhibitor with the potential for further development as a therapeutic agent for breast cancer.