Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC₅₀ = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC₅₀ = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.

组蛋白赖氨酸特异性去甲基化酶 1 (LSD1) 是一种重要的表观遗传调节剂，并以不同的方式参与恶性转化和肿瘤发病机制。因此，LSD1的抑制为癌症治疗提供了一个有吸引力的治疗靶点。基于药物再利用策略，我们筛选了我们内部针对 LSD1 的化学库，发现 EGFR 抑制剂厄洛替尼（一种 FDA 批准的肺癌药物）对 LSD1 的效力较低（IC ₅₀  = 35.80 μM）。在此，我们报告了我们进一步的药物化学努力，以获得高度水溶性的厄洛替尼类似物5k (>100 mg/mL)，其对 LSD1 的抑制活性显着增强 (IC ₅₀  = 0.69 μM) 以及更高的特异性。在 MGC-803 细胞中，5k抑制 LSD1 的去甲基化，表明其对酶的细胞活性。此外，5k具有显着的抑制集落形成、抑制迁移和诱导MGC803细胞凋亡的能力。此外，在 MGC-803 异种移植小鼠模型中，5k治疗导致肿瘤大小分别在 40 和 80 mg/kg/d 的剂量下显着减少 81.6% 和 96.1%。我们的研究结果表明，基于厄洛替尼的类似物提供了一组具有进一步研究潜力的新型结构的 LSD1 抑制剂，并可作为治疗 LSD1 过度表达癌症的新候选者。