Furtek Steffanie L, Backos Donald S, Matheson Christopher J, Reigan Philip
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Boulevard, Aurora, Colorado 80045, United States.
ACS Chem Biol. 2016 Feb 19;11(2):308-18. doi: 10.1021/acschembio.5b00945. Epub 2016 Jan 15.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates the expression of genes related to cell cycle, cell survival, and immune response associated with cancer progression and malignancy in a number of cancer types. Once activated, STAT3 forms a homodimer and translocates to the nucleus where it binds DNA promoting the translation of target genes associated with antiapoptosis, angiogenesis, and invasion/migration. In normal cells, levels of activated STAT3 remain transient; however, STAT3 remains constitutively active in approximately 70% of human solid tumors. The pivotal role of STAT3 in tumor progression has promoted a campaign in drug discovery to identify small molecules that disrupt the function of STAT3. A range of approaches have been used to identify novel small molecule inhibitors of STAT3, including high-throughput screening of chemical libraries, computational-based virtual screening, and fragment-based design strategies. The most common approaches in targeting STAT3 activity are either via the inhibition of tyrosine kinases capable of phosphorylating and thereby activating STAT3 or by preventing the formation of functional STAT3 dimers through disruption of the SH2 domains. However, the targeting of the STAT3 DNA-binding domain and disruption of binding of STAT3 to its DNA promoter have not been thoroughly examined, mainly due to the lack of adequate assay systems. This review summarizes the development of STAT3 inhibitors organized by the approach used to inhibit STAT3, the current inhibitors of each class, and the assay systems used to evaluate STAT3 inhibition and offers an insight into future approaches for small molecule STAT3 inhibitor development.
信号转导与转录激活因子3（STAT3）是一种转录因子，在多种癌症类型中，它可调节与细胞周期、细胞存活以及与癌症进展和恶性肿瘤相关的免疫反应有关的基因表达。一旦被激活，STAT3会形成同源二聚体并转移至细胞核，在细胞核中它与DNA结合，促进与抗凋亡、血管生成以及侵袭/迁移相关的靶基因的翻译。在正常细胞中，激活的STAT3水平保持短暂性；然而，在大约70%的人类实体瘤中，STAT3持续处于激活状态。STAT3在肿瘤进展中的关键作用推动了药物研发领域寻找能够破坏STAT3功能的小分子的行动。一系列方法已被用于鉴定新型STAT3小分子抑制剂，包括化学文库的高通量筛选、基于计算的虚拟筛选以及基于片段的设计策略。靶向STAT3活性最常见的方法要么是通过抑制能够磷酸化从而激活STAT3的酪氨酸激酶，要么是通过破坏SH2结构域来阻止功能性STAT3二聚体的形成。然而，针对STAT3 DNA结合结构域以及破坏STAT3与其DNA启动子结合的研究尚未得到充分探讨，主要原因是缺乏合适的检测系统。本综述总结了按抑制STAT3的方法、各类当前抑制剂以及用于评估STAT3抑制作用的检测系统来组织的STAT3抑制剂的研发情况，并对小分子STAT3抑制剂未来的研发方法提供了见解。
