Identification of Novel Phenoxazine-Derived LSD1 Inhibitors Suppressing Gastric Cancer Stemness by β-Catenin Transcriptional Regulation
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, <b>X-1</b> (IC<sub>50</sub> = 0.082 μM) emerged as the most potent, exhibiting a 3-fold improvement in activity over the previously reported compound <b>3s</b> (IC<sub>50</sub> = 0.247 μM). Mechanistic studies revealed that <b>X-1</b> suppressed the stemness of gastric cancer cells by interrupting the β-catenin-mediated transcriptional program, thereby reducing the expression of stemness-related proteins. <i>In vivo</i> studies confirmed its robust antitumor efficacy by inhibiting tumor proliferation and stemness without significant toxicity. Our findings identify <b>X-1</b> as a promising LSD1-targeted inhibitor, offering a potential therapeutic strategy for gastric cancer.
Authors
- Hai Long (ORCID: https://orcid.org/0000-0001-8590-1761)
- Shuwu Wang (ORCID: https://orcid.org/0000-0003-4877-9802)
- Xing‐Jie Dai (ORCID: https://orcid.org/0000-0001-7531-044X)
- Yi‐Chao Zheng (ORCID: https://orcid.org/0000-0002-2662-3770)
- Guo‐Liang Lu (ORCID: https://orcid.org/0000-0002-2094-0820)
- Jiayi Yin (ORCID: https://orcid.org/0000-0001-9115-4571)
- Bo Wang (ORCID: https://orcid.org/0000-0001-8149-6439)
- Huimin Liu (ORCID: https://orcid.org/0000-0001-7681-1326)
- Ning Wang (ORCID: https://orcid.org/0000-0003-1410-329X)
- Ying Liu (ORCID: https://orcid.org/0000-0002-9071-1310)
- Yan Li (ORCID: https://orcid.org/0000-0002-2781-2119)
- Hong‐Min Liu (ORCID: https://orcid.org/0000-0001-6771-9421)
- Ying Li (ORCID: https://orcid.org/0000-0002-9316-2521)
- Leipeng Xue (ORCID: https://orcid.org/0009-0002-0672-3392)
Institutions
- Ministry of Education (NZ)
- Ministry of Education of the People's Republic of China (CN)
- University of Auckland (NZ)
- Nankai University (CN)
- Prevention Institute (US)
- Zhengzhou University (CN)
- Auckland University of Technology (NZ)
- Cancer Society of New Zealand (NZ)
- Precision for Medicine (United States) (US)
- Maurice Wilkins Centre (NZ)
- Drug Discovery Laboratory (Norway) (NO)
- State Key Laboratory of Chemical Engineering (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- State Key Laboratory of Medicinal Chemical Biology
- University of Hong Kong (HK)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01798
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00