Dysregulated transcription factor activity is a defining feature of various cancer types. As such, targeting oncogenic transcriptional dependency has long been pursued as a potential therapeutic approach. However, transcription factors have historically been deemed as undruggable targets due to their highly disordered structures and lack of well-defined binding pockets. Nevertheless, interest in their pharmacologic inhibition and destruction has not dwindled in recent years. Here, we discuss new small-molecule-based approaches to target various transcription factors. Ligands with different mechanisms of action, such as inhibitors, molecular glue degraders, and proteolysis targeting chimeras, have recently seen success preclinically and clinically. We review how these strategies overcome the challenges presented by targeting transcription factors.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

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靶向转录因子的小分子方法

转录因子活性失调是各种癌症类型的一个决定性特征。因此，长期以来，靶向致癌转录依赖性一直被视为一种潜在的治疗方法。然而，转录因子历来被认为是不可成药的靶标，因为它们的结构高度无序且缺乏明确的结合袋。然而，近年来，人们对其药理抑制和破坏的兴趣并未减弱。在这里，我们讨论针对各种转录因子的新的基于小分子的方法。具有不同作用机制的配体，例如抑制剂、分子胶降解剂和靶向嵌合体的蛋白水解，最近在临床前和临床上取得了成功。我们回顾了这些策略如何克服靶向转录因子带来的挑战。《癌症生物学年度评论》第 8 卷的预计最终在线发布日期为 2024 年 4 月。请参阅 http://www.annualreviews.org/page/journal/pubdates修订后的估计。