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.