2. Academic Validation
  3. Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response

Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response

  • J Med Chem. 2023 Apr 13;66(7):4802-4826. doi: 10.1021/acs.jmedchem.2c01985.
Nan Sun 1 2,  Kexin Yang 3 4,  Wenzhong Yan 2,  Mingyue Yao 3 4 5,  Chengcheng Yu 6,  Wenwen Duan 2,  Xiaoke Gu 1,  Dong Guo 1,  Hualiang Jiang 3 4 7,  Chengying Xie 3 4 7,  Jianjun Cheng 2 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
  • 2 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 5 The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.
  • 6 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 7 Lingang Laboratory, Shanghai 200031, China.
PMID: 36934335 DOI: 10.1021/acs.jmedchem.2c01985
Abstract

Histone deacetylase (HDAC) is an epigenetic antitumor drug target, but most existing HDAC inhibitors show limited antitumor activity and their use is often accompanied by serious adverse effects. To overcome these problems, we designed and synthesized a series of triazole-containing compounds as novel HDAC inhibitors. Among them, compound 19h exhibited potent and selective inhibition of HDAC1, with good antiproliferative activity in vitro and an excellent pharmacokinetic profile. Compound 19h significantly inhibited the growth of human tumor xenografts in nude mice and murine tumor growth in immune-competent mice bearing MC38 colon Cancer. In the MC38 model, 19h increased the ratio of splenic CD4+ T effector cells and promoted complete tumor regression in 5/6 Animals when combined with the mPD-1 antibody. These results suggested that selective class I HDAC inhibitors exert direct tumor growth inhibition and indirect immune cell-mediated antitumor effects and are synergistic with immune checkpoint inhibitors.

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