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

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

  • J Med Chem. 2022 Feb 24;65(4):3667-3683. doi: 10.1021/acs.jmedchem.1c02225.
Chen Chen 1 2,  Xue Li 3,  Huajun Zhao 3,  Meng Liu 1,  Jintong Du 4,  Jian Zhang 3,  Xinying Yang 5,  Xuben Hou 1,  Hao Fang 1
Affiliations

Affiliations

  • 1 Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
  • 2 School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250012, P. R. China.
  • 3 Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
  • 4 Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, Shandong 250117, P. R. China.
  • 5 Institute of Pharmaceutical Analysis, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
PMID: 35152694 DOI: 10.1021/acs.jmedchem.1c02225
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.

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