Signal transducer and activator of transcription 3 (STAT3) is a plausible therapeutic target in the treatment of retinoblastoma, the most common intraocular malignant tumor in children. STAT3, a transcription factor of several genes related to tumorigenesis, is activated in retinoblastoma tumors as well as other cancers. In this study, we investigated the structure-activity relationship of a library of STAT3 inhibitors, including a novel series of derivatives of the previously reported compound with a Michael acceptor (compound 1). We chose two novel STAT3 inhibitors, compounds 11 and 15, from the library based on their inhibitory effects on the phosphorylation and transcription activity of STAT3. These STAT3 inhibitors effectively suppressed the phosphorylation of STAT3 and inhibited the expression of STAT3-related genes CCND1, CDKN1A, BCL2, BCL2L1, BIRC5, MYC, MMP1, MMP9, and VEGFA. Intraocularly administered STAT3 inhibitors decreased the degree of tumor formation in the vitreous cavity of BALB/c nude mice of an orthotopic transplantation model. It is noteworthy that compounds 11 and 15 did not induce in vitro and in vivo toxicity on retinal constituent cells and retinal tissues, respectively, despite their potent antitumor effects. We suggest that these novel STAT3 inhibitors be used in the treatment of retinoblastoma.

中文翻译：

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新型信号转导剂和转录激活剂 3 抑制剂对视网膜母细胞瘤的抗肿瘤活性

信号转导和转录激活因子 3 (STAT3) 是治疗视网膜母细胞瘤（儿童最常见的眼内恶性肿瘤）的合理治疗靶点。STAT3 是与肿瘤发生相关的几种基因的转录因子，在视网膜母细胞瘤和其他癌症中被激活。在这项研究中，我们研究了 STAT3 抑制剂库的构效关系，包括先前报道的具有迈克尔受体的化合物（化合物1）。我们根据对 STAT3 磷酸化和转录活性的抑制作用，从文库中选择了两种新型 STAT3 抑制剂，即化合物 11 和 15。这些 STAT3 抑制剂有效抑制 STAT3 的磷酸化并抑制 STAT3 相关基因CCND1、CDKN1A、BCL2、BCL2L1、BIRC5、MYC、MMP1、MMP9和VEGFA 的表达. 眼内施用 STAT3 抑制剂降低了原位移植模型的 BALB/c 裸鼠玻璃体腔中肿瘤的形成程度。值得注意的是，尽管化合物 11 和 15 具有有效的抗肿瘤作用，但它们并未分别对视网膜组成细胞和视网膜组织产生体外和体内毒性。我们建议将这些新型 STAT3 抑制剂用于治疗视网膜母细胞瘤。