靶向STAT3治疗癌症的策略和方法,ACS Chemical Biology

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靶向STAT3治疗癌症的策略和方法
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2016-01-15 00:00:00 , DOI: 10.1021/acschembio.5b00945
Steffanie L. Furtek ₁ , Donald S. Backos ₁ , Christopher J. Matheson ₁ , Philip Reigan ₁

Affiliation

信号转导和转录激活因子3（STAT3）是一种转录因子，可调节与多种癌症类型的细胞周期，细胞存活以及与癌症进展和恶性肿瘤相关的免疫应答相关的基因表达。STAT3一旦被激活，就会形成同型二聚体并转运至细胞核，并与DNA结合，从而促进与抗凋亡，血管生成和侵袭/迁移相关的目标基因的翻译。在正常细胞中，激活的STAT3的水平保持瞬态。然而，STAT3在约70％的人类实体瘤中仍具有组成型活性。STAT3在肿瘤进展中的关键作用促进了药物发现运动，以鉴定破坏STAT3功能的小分子。已经使用了多种方法来鉴定STAT3的新型小分子抑制剂，包括化学库的高通量筛选，基于计算的虚拟筛选和基于片段的设计策略。靶向STAT3活性的最常见方法是通过抑制能够磷酸化从而激活STAT3的酪氨酸激酶，或通过破坏SH2结构域来防止功能性STAT3二聚体的形成。然而，主要由于缺乏适当的测定系统，尚未对STAT3 DNA结合结构域的靶向和STAT3与其DNA启动子的结合破坏进行彻底检查。这篇综述总结了STAT3抑制剂的开发情况，该抑制剂是通过抑制STAT3的方法来组织的，STAT3是目前每种药物的抑制剂，

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Strategies and Approaches of Targeting STAT3 for Cancer Treatment

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.

更新日期：2016-01-15

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