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Preclinical and Clinical Advances of Targeted Protein Degradation as a Novel Cancer Therapeutic Strategy: An Oncologist Perspective

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Abstract

PROteolysis Targeting Chimeras (PROTACs) are a family of heterobifunctional small molecules that specifically target cellular proteins for degradation. Given that their mode of action is distinct from that of small-molecule inhibitors widely used in clinical practice, PROTACs have the potential to improve current cancer therapies. Multiple studies have suggested that PROTACs exhibit enhanced pharmacodynamics and reduced toxicity both in vitro and in vivo compared to clinically relevant small-molecule kinase inhibitors. In addition, PROTACs have been reported to be less prone to mutation-mediated drug resistance in specific disease settings. Since its development in 2001, the field of targeted protein degradation, in which PROTACs are used, has expanded rapidly. However, earlier studies focused on the advancement of the technology itself, while preclinical and clinical data on the disease-modifying effect of PROTACs have only recently been reported. As preclinical and clinical evidence accumulates, the efficacy of PROTACs as targeted therapeutics—distinct from that of small-molecule kinase inhibitors—suggests potential translational benefit in the clinical setting. In this short review, we aim to describe translational potentials of PROTACs. We offer our perspectives as practicing oncologists on the preclinical and clinical data on PROTACs as novel therapeutics for both solid and hematological malignancies.

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Acknowledgements

Editorial assistance was provided by the Moffitt Cancer Center’s Office of Scientific Writing by Dr. Paul Fletcher and Daley Drucker. No compensation was given beyond their regular salaries.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Xinrui Yang, He Yin, Richard D. Kim, Jason B. Fleming & Hao Xie

  2. Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Richard D. Kim, Jason B. Fleming & Hao Xie

Authors
  1. Xinrui Yang
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  2. He Yin
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  3. Richard D. Kim
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  4. Jason B. Fleming
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  5. Hao Xie
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Corresponding author

Correspondence to Hao Xie.

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Funding

A support grant was received by Dr. Hao Xie from H. Lee Moffitt Cancer Center & Research Institute.

Conflict of interest

The authors, Xinrui Yang, He Yin, Richard D. Kim, Jason B. Fleming, and Hao Xie, declare that they have no conflicts of interest that might be relevant to the contents of this article.

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XY contributed to formulating the idea for the manuscript and writing and editing. HX contributed to formulating the idea for the manuscript and editing. HY, RDK, and JBF participated in editing the manuscript.

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Yang, X., Yin, H., Kim, R.D. et al. Preclinical and Clinical Advances of Targeted Protein Degradation as a Novel Cancer Therapeutic Strategy: An Oncologist Perspective. Targ Oncol 16, 1–12 (2021). https://doi.org/10.1007/s11523-020-00782-2

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  • DOI: https://doi.org/10.1007/s11523-020-00782-2

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