Department of Chemical and Physical Sciences, University of Toronto Mississauga , 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6.
J Med Chem. 2013 Sep 26;56(18):7190-200. doi: 10.1021/jm3017255. Epub 2013 Sep 13.
The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3-4 years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3's SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.
信号转导子和转录激活子（STAT）蛋白家族是一类细胞质转录因子，可调节多种生物学过程。特别是 Stat3 蛋白，因其调节多种恶性过程中基因的表达而备受关注，这些过程包括增殖、存活、迁移和耐药性。多发性骨髓瘤（MM）是一种不可治愈的血液恶性肿瘤，其 Stat3 活性通常异常升高。尽管目前的治疗策略可以改善 MM 的临床管理，但它仍然无法治愈，治疗后中位生存时间为 3-4 年。因此，迫切需要新的靶向治疗药物来改善 MM 患者的预后。我们在此报告了一系列具有体外强效抗 MM 活性的小分子 Stat3 抑制剂的开发。这些化合物与 Stat3 的 SH2 结构域具有高亲和力，可抑制细胞内 Stat3 磷酸化，并在低微摩尔浓度下诱导 MM 细胞系凋亡。
