As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.

作为一类天然存在的基因调节因子，microRNA (miRNA) 作为治疗开发的有希望的靶点而备受关注。然而，包括 miRNA 在内的 RNA 长期以来一直被认为是不可成药的，并且大多数努力都致力于使用合成寡核苷酸来调节 miRNA。令人鼓舞的是，最近的研究结果表明，miRNA 也可以用直接靶向 miRNA 的小分子进行药物治疗。在这篇综述论文中，我们总结了最近出现的 miRNA 小分子抑制剂 (SMI) 和小分子降解剂 (SMD)。 SMI 是直接与 miRNA 结合以抑制其生物发生的小分子，而 SMD 是双功能小分子，在与 miRNA 结合后诱导 miRNA 降解。总结了发现 SMI 和开发 SMD 的策略。还介绍了SMI和SMD在miRNA抑制和癌症治疗中的应用。总体而言，本文介绍的 SMI 和 SMD 在 miRNA 抑制方面具有高效能和特异性。我们设想这些小分子将为开发针对以前被认为不可成药的 miRNA 的新型疗法铺平道路。