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

Xing-Jie Dai; Ying Liu; Ning Wang; He-Xiang Chen; Jiang-Wan Wu; Xiao-Peng Xiong; Shi-Kun Ji; Ying Zhou; Liang Shen; Shao-Peng Wang; Hong-Min Liu; Hui-Min Liu; Yi-Chao Zheng

doi:10.1016/j.ejmech.2023.115684

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. Epub 2023 Jul 29.

Authors

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.

MeSH terms

Acridines / pharmacology
Animals
Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Enzyme Inhibitors / pharmacology
Histone Demethylases
Immunity
Mice
Molecular Docking Simulation
Stomach Neoplasms* / drug therapy
Structure-Activity Relationship

Substances

Antineoplastic Agents
Acridines
Histone Demethylases
Enzyme Inhibitors