Identification of Novel Phenoxazine-Derived LSD1 Inhibitors Suppressing Gastric Cancer Stemness by β-Catenin
Xing-Jie Dai1, Leipeng Xue1,2, Ying Liu3
1State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; Key Laboratory of Henan Province for Small Molecule Drug Discovery and Application; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.
Abstract:
Lysine-specific demethylase 1 (LSD1) is a validated cancer therapeutic target, critically implicated in maintaining cancer stem cells (CSCs) across leukemia and solid tumors. Although numerous potent LSD1 inhibitors have been developed, none have reached clinical approval, underscoring the need for novel agents with improved efficacy. Using a scaffold-hopping strategy, we designed and synthesized a novel class of phenoxazine-based LSD1 inhibitors. Among them, X-1 (IC50 = 0.082 μM) emerged as the most potent, exhibiting a 3-fold improvement in activity over the previously reported compound 3s (IC50 = 0.247 μM). Mechanistic studies revealed that X-1 suppressed the stemness of gastric cancer cells by interrupting the β-catenin-mediated transcriptional program, thereby reducing the expression of stemness-related proteins. In vivo studies confirmed its robust antitumor efficacy by inhibiting tumor proliferation and stemness without significant toxicity. Our findings identify X-1 as a promising LSD1-targeted inhibitor, offering a potential therapeutic strategy for gastric cancer.
Insights
A novel phenoxazine-based compound, X-1, effectively inhibits lysine-specific demethylase 1 (LSD1) and suppresses cancer stemness in gastric cancer models. This potent inhibitor shows promise as a new therapeutic strategy for treating this disease.
Area of Science:
- Oncology
- Medicinal Chemistry
Background:
- Lysine-specific demethylase 1 (LSD1) is crucial for cancer stem cell (CSC) maintenance and a validated therapeutic target.
- Existing LSD1 inhibitors lack clinical approval, highlighting the need for more effective agents.
Purpose of the Study:
- To design and synthesize novel phenoxazine-based LSD1 inhibitors with improved efficacy.
- To evaluate the therapeutic potential of the lead compound X-1 in gastric cancer.
Main Methods:
- Scaffold-hopping strategy was employed to design and synthesize novel phenoxazine-based compounds.
- In vitro assays determined the inhibitory activity (IC50) of compounds against LSD1.
- Mechanistic studies investigated the effect of X-1 on stemness pathways in gastric cancer cells.
- In vivo studies assessed the antitumor efficacy and toxicity of X-1 in preclinical models.
Main Results:
- Compound X-1 demonstrated potent LSD1 inhibition (IC50 = 0.082 μM), showing a 3-fold improvement over compound 3s.
- X-1 effectively suppressed gastric cancer cell stemness by disrupting the β-catenin pathway.
- In vivo studies confirmed X-1's ability to inhibit tumor proliferation and stemness with minimal toxicity.
Conclusions:
- X-1 represents a novel and potent class of phenoxazine-based LSD1 inhibitors.
- X-1 exhibits significant preclinical efficacy against gastric cancer by targeting CSCs.
- X-1 is a promising candidate for further development as a targeted therapy for gastric cancer.
More Related Videos
13:38Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
06:00Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
Published on: May 14, 2016
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...