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Discovery of acridine-based LSD1 inhibitors as immune activators targeting LSD1 in gastric cancer
Hui-Min Liu1, Xiao-Peng Xiong1, Jiang-Wan Wu1
1State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
Abstract:
LSD1 is overexpressed in various cancers and promotes tumor cell proliferation, tumor expansion, and suppresses immune cells infiltration and is closely associated with immune checkpoint inhibitors therapy. Therefore, the inhibition of LSD1 has been recognized as a promising strategy for cancer therapy. In this study, we screened an in-house small-molecule library targeting LSD1, an FDA-approved drug amsacrine for acute leukemia and malignant lymphomas was found to exhibit moderate anti-LSD1 inhibitory activity (IC50 = 0.88 μM). Through further medicinal chemistry efforts, the most active compound 6x increased anti-LSD1 activity significantly (IC50 = 0.073 μM). Further mechanistic studies demonstrated that compound 6x inhibited the stemness and migration of gastric cancer cell, and decreased the expression of PD-L1 (programmed cell death-ligand 1) in BGC-823 and MFC cells. More importantly, BGC-823 cells are more susceptible to T-cell killing when treated with compound 6x. Moreover, tumor growth was also suppressed by compound 6x in mice. Altogether, our findings demonstrated that acridine-based novel LSD1 inhibitor 6x may be a lead compound for the development of activating T cell immune response in gastric cancer cells.
Insights
A novel compound, 6x, effectively inhibits LSD1, a protein overexpressed in cancers. This new inhibitor shows promise in gastric cancer therapy by enhancing T cell immune response and suppressing tumor growth.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Lysine-specific demethylase 1 (LSD1) is overexpressed in various cancers, promoting tumor progression and immune suppression.
- LSD1 inhibition is a promising strategy for cancer therapy, particularly in conjunction with immune checkpoint inhibitors.
- Amsacrine, an FDA-approved drug, showed moderate anti-LSD1 activity, prompting further investigation.
Purpose of the Study:
- To identify and develop novel small-molecule inhibitors targeting LSD1.
- To evaluate the efficacy of a novel compound, 6x, in inhibiting LSD1 and its downstream effects in gastric cancer.
- To assess the potential of 6x in enhancing anti-tumor immune responses.
Main Methods:
- Screening of an in-house small-molecule library for LSD1 inhibitors.
- Medicinal chemistry optimization to enhance anti-LSD1 activity.
- In vitro studies on gastric cancer cell lines (BGC-823, MFC) to assess stemness, migration, and PD-L1 expression.
- In vitro T-cell killing assays.
- In vivo studies using mouse models to evaluate tumor growth suppression.
Main Results:
- Compound 6x demonstrated significantly enhanced anti-LSD1 inhibitory activity (IC50 = 0.073 μM) compared to amsacrine (IC50 = 0.88 μM).
- 6x inhibited stemness and migration of gastric cancer cells and decreased programmed cell death-ligand 1 (PD-L1) expression.
- Treatment with 6x increased the susceptibility of BGC-823 cells to T-cell killing and suppressed tumor growth in mice.
Conclusions:
- Acridine-based novel LSD1 inhibitor 6x is a potent compound with anti-cancer properties.
- 6x shows potential for developing therapies that activate T cell immune responses in gastric cancer.
- Further development of 6x could lead to new treatment strategies for gastric cancer and potentially other LSD1-overexpressing malignancies.
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