Signal transducer and activator of transcription 3 (STAT3) is a member of the transcription factors involved in regulating many physiological and pathological processes, such as cell proliferation, angiogenesis and immune escape. STAT3 has been identified as a potential therapeutic target for various cancers. Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity, they are not yet authorized for clinical use and only a few have entered clinical trials. Furthermore, several proteolysis-targeting chimera (PROTAC) molecules with STAT3 degrading effects have been developed. The event-driven action of PROTAC overcome the drawbacks of STAT3, a traditional undruggable target, and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein. In this review, we presented a brief introduction to STAT3 and its functions in various cancers, and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years, the structural characterization of the main scaffold, the design strategies, and the pharmacological activities of the substituents. Also, the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized. We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.

中文翻译：

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靶向 STAT3 的小分子抑制剂和降解剂用于癌症治疗的更新综述（2022 年至 2024 年）


信号转导和转录激活因子 3 （STAT3） 是转录因子的一员，参与调节许多生理和病理过程，例如细胞增殖、血管生成和免疫逃逸。STAT3 已被确定为各种癌症的潜在治疗靶点。尽管已经发现并优化了许多 STAT3 抑制剂以直接抑制 STAT3 活性，但它们尚未被授权用于临床，只有少数进入临床试验。此外，已经开发了几种具有 STAT3 降解作用的蛋白水解靶向嵌合体 （PROTAC） 分子。PROTAC 的事件驱动作用克服了 STAT3 （一种传统的不可成药靶标）的缺点，并通过降解整个 STAT3 蛋白解决了对小分子抑制剂的可能耐药性。在这篇综述中，我们简要介绍了 STAT3 及其在各种癌症中的功能，并系统地概述了过去三年中靶向 STAT3 不同结构域的抑制剂的药理作用、主要支架的结构表征、设计策略和取代基的药理活性。此外，还详细分析了一些抑制剂与 STAT3 的结合模式和相互作用，并总结了 STAT3 降解剂的最新进展。我们预计这一观点将有助于设计和优化用于癌症治疗的更新颖、有效和特异性的 STAT3 抑制剂或降解剂。