Department of Chemistry, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, Canada L5L 1C6.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5605-9. doi: 10.1016/j.bmcl.2011.06.056. Epub 2011 Jun 30.
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 (K(i)=13 μM), inhibited Stat3-Stat3 protein interactions (IC(50)=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 (EC(50)=10 and 16 μM, respectively).
信号转导子和转录激活子 3（Stat3）蛋白是一种细胞浆转录因子，在许多人类癌症中异常激活。已经表明，激活的 Stat3-Stat3 蛋白复合物抑制剂在治疗携带激活的 Stat3 的人类癌症方面具有治疗潜力。在此，我们报告了一个包含 Stat3 SH2 结构域结合物的水杨酸的聚焦文库的设计和合成。最有效的抑制剂 17o，有效地破坏了 Stat3-磷酸肽复合物（K(i)=13 μM），抑制了 Stat3-Stat3 蛋白相互作用（IC(50)=19 μM），并沉默了细胞内 Stat3 磷酸化和 Stat3-靶基因表达谱。Stat3 功能的抑制在乳腺癌和多发性骨髓瘤（MM）肿瘤细胞中与诱导的细胞死亡相关（EC(50)=10 和 16 μM，分别）。
