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, 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.