Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling promotes tumorigenesis and cancer progression. STAT3 participates in the essential processes of cell proliferation, survival, and differentiation in many types of tumors. In the present study, SP2509 was identified as a potent inhibitor of the JAK/STAT3 signaling pathway by high-throughput drug screening based on a STAT3-driven luciferase expression system. Our results indicated that SP2509 inhibits constitutive STAT3 activation and the expression of STAT3-driven downstream genes. Bcl-xL, c-Myc, and Cyclin D1 were downregulated after treatment with SP2509. In addition, SP2509 specifically inhibits JAK activity, which could cause cell cycle arrest, inhibit cell growth, and induce apoptosis of various cancer cells. These results confirmed that SP2509 inhibits tumor progression by suppressing the expression of JAK/STAT3 signaling and STAT3-related downstream genes. Moreover, we demonstrated that SP2509 inhibits tumor growth in vivo and induces cell death in vitro. SP2509-mediated inhibition of STAT3 phosphorylation is dependent on its original target lysine-specific demethylase 1 in cancer cells. In summary, our results indicate that SP2509 is a novel inhibitor of JAK/STAT3 signaling.

中文翻译：

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SP2509 是 LSD1 的抑制剂，通过靶向 JAK/STAT3 信号发挥潜在的抗肿瘤作用

Janus 激酶 (JAK)/信号转导和转录激活因子 (STAT) 信号的过度激活促进肿瘤发生和癌症进展。STAT3 参与多种类型肿瘤中细胞增殖、存活和分化的基本过程。在本研究中，通过基于 STAT3 驱动的荧光素酶表达系统的高通量药物筛选，SP2509 被鉴定为 JAK/STAT3 信号通路的有效抑制剂。我们的结果表明 SP2509 抑制组成型 STAT3 激活和 STAT3 驱动的下游基因的表达。Bcl-xL、c-Myc 和细胞周期蛋白 D1 在用 SP2509 处理后下调。此外，SP2509 特异性抑制 JAK 活性，这可能导致细胞周期停滞，抑制细胞生长，并诱导各种癌细胞凋亡。这些结果证实，SP2509 通过抑制 JAK/STAT3 信号传导和 STAT3 相关下游基因的表达来抑制肿瘤进展。此外，我们证明了 SP2509 抑制肿瘤生长在体内并在体外诱导细胞死亡。SP2509 介导的 STAT3 磷酸化抑制取决于其在癌细胞中的原始目标赖氨酸特异性脱甲基酶 1。总之，我们的结果表明 SP2509 是一种新型 JAK/STAT3 信号抑制剂。