2. Academic Validation
  3. Identification of Novel Phenoxazine-Derived LSD1 Inhibitors Suppressing Gastric Cancer Stemness by β-Catenin Transcriptional Regulation

Identification of Novel Phenoxazine-Derived LSD1 Inhibitors Suppressing Gastric Cancer Stemness by β-Catenin Transcriptional Regulation

  • J Med Chem. 2025 Nov 13;68(21):22896-22917. doi: 10.1021/acs.jmedchem.5c01798.
Xing-Jie Dai 1,  Leipeng Xue 1 2,  Ying Liu 3,  Shu-Wu Wang 1,  Ying Li 1,  Jia-Yi Yin 1,  Hao-Zhe Long 1,  Hui-Min Liu 1,  Ning Wang 4,  Guo-Liang Lu 5 6,  Yan Li 6 7,  Hong-Min Liu 1,  Bo Wang 1,  Yi-Chao Zheng 1
Affiliations

Affiliations

  • 1 State 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.
  • 2 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China.
  • 3 Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 4 School of Chinese Medicine, the University of Hong Kong, 3, Sasson Road, Pokfulam, Kowloon 999077, Hong Kong.
  • 5 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 6 Maurice Wilkins Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 7 Department of Biomedicine and Medical Diagnostics, School of Science, Auckland University of Technology, 34 St. Paul Street, Auckland 1010, New Zealand.
PMID: 41159872 DOI: 10.1021/acs.jmedchem.5c01798
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.

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