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Drugging the “undruggable” microRNAs

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Abstract

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.

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Author notes

  1. Dejun Liu, Xinqiang Wan, and Xiangxiang Shan contributed equally.

Authors and Affiliations

  1. The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224001, China

    Dejun Liu

  2. Department of Gynaecology and Obstetrics, Yancheng City No.1 People’s Hospital, Yancheng, 224001, China

    Xinqiang Wan

  3. Department of Geraeology, Yancheng City No.1 People’s Hospital, Yancheng, 224001, China

    Xiangxiang Shan

  4. Department of General Surgery, Yancheng City No.1 People’s Hospital, Yancheng, 224001, China

    Rengen Fan & Wenzhang Zha

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  1. Dejun Liu
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Liu, D., Wan, X., Shan, X. et al. Drugging the “undruggable” microRNAs. Cell. Mol. Life Sci. 78, 1861–1871 (2021). https://doi.org/10.1007/s00018-020-03676-8

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