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Smart PROTACs Enable Controllable Protein Degradation for Precision Cancer Therapy

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Abstract

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional chemicals that degrade proteins at the post-translational level, which represent an emerging therapeutic modality to fight cancer and other diseases. Although several PROTACs have now entered clinical trials, potential off-tissue side effects have resulted from nonspecific accumulation at non-cancerous sites after systemic administration, and this remains a major challenge. To this end, in the past 3 years, activatable PROTACs whose activity can only be launched on demand have gained tremendous momentum. In this review, we provide an overview of these new smart activatable PROTACs, which exert protein degradation action only in response to internal or external stimuli. We categorize these activatable PROTACs according to their activation mechanism contributed by different stimuli, including reduction-activatable, hypoxia-activatable, and enzyme-activatable PROTACs and photo-caged or photo-switchable PROTACs. The use of stimuli-responsive chemical blocks in these activatable PROTACs allows local activation of the antitumor effects while reducing the incidence of off-site side effects for precision cancer therapy. The design principle and category of smart PROTACs are introduced along with an overview of their therapeutic prospects and challenges.

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Author notes

  1. Lixia Chen, Xinqiang Wan and Xiangxiang Shan contributed equally.

Authors and Affiliations

  1. Medical College of Nantong University, Nantong, China

    Lixia Chen

  2. Department of Gynaecology and Obstetrics, The Fourth Affiliated Hospital of Nantong University, The First People’s Hospital of Yancheng, Yancheng, China

    Xinqiang Wan

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

    Xiangxiang Shan

  4. Department of General Surgery, The Fourth Affiliated Hospital of Nantong University, The First People’s Hospital of Yancheng, 166 Yulong Road, Yancheng, 224001, China

    Wenzhang Zha & Rengen Fan

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  1. Lixia Chen
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Correspondence to Rengen Fan.

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L. Chen, X. Wan, and X. Shan wrote the manuscript and prepared the figures with equal contributions. W. Zha proofread the manuscript. R. Fan raised the concept, conducted the literature review, and wrote and revised the manuscript and figures. All authors approved the final manuscript.

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Chen, L., Wan, X., Shan, X. et al. Smart PROTACs Enable Controllable Protein Degradation for Precision Cancer Therapy. Mol Diagn Ther 26, 283–291 (2022). https://doi.org/10.1007/s40291-022-00586-2

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