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

Authors :
Chen C
Li X
Zhao H
Liu M
Du J
Zhang J
Yang X
Hou X
Fang H
Source :
Journal of medicinal chemistry [J Med Chem] 2022 Feb 24; Vol. 65 (4), pp. 3667-3683. Date of Electronic Publication: 2022 Feb 12.
Publication Year :
2022

Abstract

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
65
Issue :
4
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
35152694
Full Text :
https://doi.org/10.1021/acs.jmedchem.1c02225