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Phenothiazine-Based LSD1 Inhibitor Promotes T-Cell Killing Response of Gastric Cancer Cells
Xing-Jie Dai1, Li-Juan Zhao1,2, Long-Hua Yang1
1Key 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, China.
Abstract:
Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 μM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 μM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.
Insights
Researchers identified chlorpromazine derivatives as potent inhibitors of Histone Lysine Specific Demethylase 1 (LSD1). Compound 3s, a novel LSD1 inhibitor, demonstrated efficacy in preclinical gastric cancer models by enhancing T-cell responses.
Area of Science:
- Biochemistry
- Epigenetics
- Cancer Biology
Background:
- Histone Lysine Specific Demethylase 1 (LSD1) is a key epigenetic regulator and a validated target for cancer therapy.
- Existing LSD1 inhibitors are progressing in clinical trials, but the need for novel, more potent compounds persists.
- The phenothiazine scaffold, found in antipsychotic drugs, represents an underexplored structural class for LSD1 inhibitor development.
Purpose of the Study:
- To identify novel LSD1 inhibitors based on the chlorpromazine scaffold.
- To evaluate the anticancer efficacy of a lead compound, 3s, in preclinical gastric cancer models.
- To investigate the mechanism of action of compound 3s, focusing on its effects on programmed cell death-ligand 1 (PD-L1) expression and T-cell activity.
Main Methods:
- Characterization of chlorpromazine as an LSD1 inhibitor and synthesis of its derivatives.
- In vitro enzymatic assays to determine inhibitory potency (IC50 values).
- Cellular assays to assess LSD1 inhibition, PD-L1 downregulation, and T-cell mediated cytotoxicity.
- In vivo studies in immunocompetent mice to evaluate tumor growth inhibition and toxicity.
Main Results:
- Chlorpromazine was identified as an LSD1 inhibitor with an IC50 of 5.135 μM.
- Compound 3s, a synthesized derivative, exhibited significantly enhanced potency (IC50 = 0.247 μM).
- Compound 3s effectively inhibited LSD1 in cancer cells, downregulated PD-L1 expression, enhanced T-cell killing, and suppressed tumor growth in vivo without significant toxicity.
Conclusions:
- Compound 3s, a novel phenothiazine-based LSD1 inhibitor, shows promising preclinical efficacy in gastric cancer.
- 3s demonstrates potential for reactivating anti-tumor T-cell immunity by downregulating PD-L1.
- This study highlights the therapeutic potential of 3s as a lead compound for gastric cancer treatment and immunotherapy.
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