The aberrant activation of a signal transducer and activator of transcription 3 (STAT3) restrains type I interferon (IFN) α/β-induced antiviral responses and is associated with the development of cancer. Designing specific STAT3 inhibitors will thus provide new options for use as IFN therapy. Herein, we identified a novel small molecule, dimethyl 2-(4-(2-(methyl(phenyl(p-tolyl)methyl)amino)ethoxy)benzyl)malonate (CIB-6), which can inhibit the IFN-α-induced interferon stimulated response element (ISRE) luciferase reporter (IC₅₀ value = 6.4 μM) and potentiate the antiproliferative effect of IFN-α in human hepatocellular carcinoma (HCC) cells. CIB-6 was found to bind to the STAT3 Src homology 2 (SH2) domain, thereby selectively inhibiting STAT3 phosphorylation without affecting Janus kinases and STAT1/2. CIB-6 also inhibited the migration and invasion of HCC cells by inhibiting the epithelial–mesenchymal transition (EMT) process. Mechanistically, CIB-6 reduced the expression of β-catenin (an EMT key protein) via upregulating β-transducin repeat-containing protein (β-TrCP) and curbed nuclear factor kappa-B (NF-κB) activation through restricting the phosphorylation of the inhibitor of NF-κB (IκB) kinase (IKK) via STAT3 inhibition. Treatment with CIB-6 significantly retarded tumor growth in nude mice with SK-HEP-1 xenografts. In addition, clinical sample analysis revealed that lower β-TrCP and higher β-catenin expression could affect the median survival time of HCC patients. Our findings suggest that CIB-6 could be a new therapeutic strategy for HCC therapy through STAT3-mediated β-TrCP/β-catenin/NF-κB axis.

中文翻译：

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2-苄基丙二酸酯衍生物作为STAT3抑制剂通过上调β-TrCPE3泛素连接酶抑制肝癌中的肿瘤生长。

信号转导子和转录激活子3（STAT3）的异常激活抑制了I型干扰素（IFN）α/β诱导的抗病毒反应，并且与癌症的发展有关。因此，设计特定的STAT3抑制剂将为用作IFN治疗提供新的选择。在这里，我们确定了一种新型的小分子2-（4-（2-（甲基（苯基（对甲苯基）甲基）氨基）乙氧基）苄基）丙二酸二甲酯（CIB-6），它可以抑制IFN-α-诱导的干扰素刺激反应元件（ISRE）荧光素酶报告基因（IC ₅₀值= 6.4μM）并增强IFN-α在人肝细胞癌（HCC）细胞中的抗增殖作用。发现CIB-6与STAT3 Src同源2（SH2）域结合，从而选择性抑制STAT3磷酸化而不影响Janus激酶和STAT1 / 2。CIB-6还通过抑制上皮-间质转化（EMT）过程来抑制HCC细胞的迁移和侵袭。从机理上讲，CIB-6通过上调包含β-转导蛋白重复序列​​的蛋白（β-TrCP）和抑制核因子kappa-B（NF-κB）的活化来抑制β-catenin（一种EMT关键蛋白）的表达，从而限制了其磷酸化STAT3抑制NF-κB（IκB）激酶（IKK）的抑制剂。用CIB-6处理可显着抑制SK-HEP-1异种移植裸鼠的肿瘤生长。此外，临床样本分析显示，较低的β-TrCP和较高的β-catenin表达可能会影响肝癌患者的中位生存时间。我们的发现表明CIB-6可能是通过STAT3介导的β-TrCP/β-catenin/NF-κB轴进行HCC治疗的新治疗策略。