Development\nof a First-in-Class DNMT1/HDAC Inhibitor\nwith Improved Therapeutic Potential and Potentiated Antitumor Immunity

Epigenetic\ntherapies have emerged as a key paradigm for\ntreating\nmalignancies. In this study, a series of DNMT1/HDAC dual inhibitors\nwere obtained by fusing the key pharmacophores from DNMT1 inhibitors\n(DNMT1i) and HDAC inhibitors (HDACi). Among them, compound <b>(</b><i><b>R</b></i><b>)</b>-<b>23a</b> demonstrated\nsignificant DNMT1 and HDAC inhibition both in vitro and in cells and\nlargely phenocopied the synergistic effects of combined DNMT1i and\nHDACi in reactivating epigenetically silenced tumor suppressor genes\n(TSGs). This translated into a profound tumor growth inhibition (TGI\n= 98%) of <b>(</b><i><b>R</b></i><b>)</b>-<b>23a</b> in an MV-4-11 xenograft model, while displaying\nimproved tolerability compared with single agent combination. Moreover,\nin a syngeneic MC38 mouse colorectal tumor model, <b>(</b><i><b>R</b></i><b>)</b>-<b>23a</b> outperformed\nthe combinatory treatment in reshaping the tumor immune microenvironment\nand inducing tumor regression. Collectively, the novel DNMT1/HDAC\ndual inhibitor <b>(</b><i><b>R</b></i><b>)</b>-<b>23a</b> effectively reverses the cancer-specific\nepigenetic abnormalities and holds great potential for further development\ninto cancer therapeutic agents.