Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway
Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway
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DOI：
10.1021/acsmedchemlett.5b00228
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发表时间：
2015-09-01
影响因子：
4.2
通讯作者：
Qiao, Chunhua
中科院分区：
文献类型：
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作者：
Ji, Peng;Xu, Xin;Qiao, Chunhua
信号转导和转录激活因子3(STAT3)被认为是肿瘤治疗的一个有吸引力的治疗靶点。在本研究中，设计了一系列2-羰基苯并[b]噻吩类1，1-二氧化物(CBT)来抑制STAT3SH2结构域的磷酸化位点Try 705。我们证明了通过酰胺键连接到苯并[b]噻吩基1，1-二氧化物(BTP)上的碱性柔性基团可以得到比BTP本身更强的抗增殖活性的化合物。荧光素酶报告基因分析表明，最有效的化合物6O通过降低STAT3 Tyr705的磷酸化水平来抑制STAT3途径，而该途径中其他上游酪氨酸激酶的磷酸化水平并未受到明显抑制。化合物6O也被证明触发ROS的产生和积累，因此部分归因于观察到的细胞凋亡。这项研究为开发针对STAT3途径的抑制剂提供了重要的结构信息。
Signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for cancer therapy. In this study, a series of 2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives (CBT) were designed to inhibit the STAT3 SH2 domain phosphorylation site Try 705. We demonstrated that incorporation of basic flexible groups through amide bond linkage to benzo[b]thiophene 1,1-dioxide (BTP) achieved compounds with higher antiproliferative potency than BTP itself. The most potent compound 6o, as indicated from luciferase reporter gene assay, inhibited the STAT3 pathway by decreasing the phosphorylation level of STAT3 Tyr705, while the phosphorylation level of other upstream tyrosine kinases in this pathway was not significantly inhibited. Compound 6o was also shown to trigger ROS generation and accumulation, thus consequently attributed partially to the observed cell apoptosis. This study provided important structural information for the development of inhibitors targeting the STAT3 pathway.