Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity

Epigenetic
therapies have emerged as a key paradigm for
treating
malignancies. In this study, a series of DNMT1/HDAC dual inhibitors
were obtained by fusing the key pharmacophores from DNMT1 inhibitors
(DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated
significant DNMT1 and HDAC inhibition both in vitro and in cells and
largely phenocopied the synergistic effects of combined DNMT1i and
HDACi in reactivating epigenetically silenced tumor suppressor genes
(TSGs). This translated into a profound tumor growth inhibition (TGI
= 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying
improved tolerability compared with single agent combination. Moreover,
in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed
the combinatory treatment in reshaping the tumor immune microenvironment
and inducing tumor regression. Collectively, the novel DNMT1/HDAC
dual inhibitor (R)-23a effectively reverses the cancer-specific
epigenetic abnormalities and holds great potential for further development
into cancer therapeutic agents.