Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.
Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.
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DOI：
10.1016/j.bmcl.2011.06.056
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发表时间：
2011-09-15
影响因子：
2.7
通讯作者：
Gunning PT
中科院分区：
文献类型：
--
作者：
Page BD;Fletcher S;Yue P;Li Z;Zhang X;Sharmeen S;Datti A;Wrana JL;Trudel S;Schimmer AD;Turkson J;Gunning PT
信号转导和转录激活因子3(STAT3)蛋白是一种胞质转录因子，在多种人类肿瘤中被异常激活。激活的STAT3-STAT3蛋白复合体的抑制剂已被证明对携带激活的STAT3的人类癌症具有治疗前景。在这里，我们报道了一个含有STAT3SH2结构域结合的水杨酸的设计和合成。最有效的抑制剂17O有效地破坏了STAT3：磷酸肽复合体(Ki=13μM)，抑制了STAT3-STAT3蛋白相互作用(IC50=19μM)，并沉默了细胞内STAT3磷酸化和STAT3靶基因表达谱。乳腺癌和多发性骨髓瘤(MM)肿瘤细胞中STAT3功能的抑制与诱导细胞死亡有关(EC_(50)分别为10μM和16μM)。
Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3–Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3:phosphopeptide complexes (Ki = 13 μM), inhibited Stat3–Stat3 protein interactions (IC50 = 19 μM) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC50 = 10 μM and 16 μM, respectively).