Discovery of DNA-Targeting HDAC Inhibitors with Potent Antitumor Efficacy In Vivo That Trigger Antitumor Immunity

We observed a synergistic antiproliferation
effect with combined
use of a DNA minor groove binder and a histone deacetylase (HDAC)
inhibitor. Inspired by this result, a new series of benzimidazole–hydroxamate hybrids were designed and synthesized
to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory
activities compared to SAHA but also possessed potent antiproliferation
activities against tumor cells. Importantly, compounds 9k and 9l showed good in vivo antitumor efficacies in
both HEL xenograft model and murine melanoma model. We also found
that 9k and 9l promote the antigen presentation
and activate T cells, thereby triggering antitumor immunity. Moreover,
these inhibitors reshaped the tumor immune microenvironment by inhibiting
the recruitment of Treg cells and promoting the polarization of tumor-infiltrating
macrophages to M2 type with antitumor activity. Our study validated
the effectiveness of incorporating a DNA-binding fragment in HDAC
inhibitors as novel multitargeting antitumor agents.