2. Academic Validation
  3. Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer

Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer

  • Eur J Med Chem. 2023 Nov 5;259:115684. doi: 10.1016/j.ejmech.2023.115684.
Xing-Jie Dai 1,  Ying Liu 2,  Ning Wang 3,  He-Xiang Chen 1,  Jiang-Wan Wu 1,  Xiao-Peng Xiong 1,  Shi-Kun Ji 1,  Ying Zhou 1,  Liang Shen 1,  Shao-Peng Wang 1,  Hong-Min Liu 1,  Hui-Min Liu 4,  Yi-Chao Zheng 5
Affiliations

Affiliations

  • 1 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China.
  • 2 Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, China.
  • 3 The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
  • 4 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China. Electronic address: liuhuimin@zzu.edu.cn.
  • 5 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China. Electronic address: yichaozheng@zzu.edu.cn.
PMID: 37542989 DOI: 10.1016/j.ejmech.2023.115684
Abstract

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for Cancer Immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 73 nM). Molecular docking studies revealed that compound 5ac could DOCK well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric Cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric Cancer.

Keywords

Acridine; Gastric cancer; Immune response; Inhibitor; LSD1.

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