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Annual Review of Cancer Biology

Volume 9, 2025

Development of PROTAC Degrader Drugs for Cancer

  • Vesna Vetma1,*, Suzanne O'Connor1,* and Alessio Ciulli1
  • Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, United Kingdom; email: [email protected]
    * These authors contributed equally to this article
  • Vol. 9:119-140 (Volume publication date April 2025)
  • First published as a Review in Advance on October 30, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The development of novel drug modalities is necessary to overcome the current critical issues in the treatment of cancer, namely toxicity, insufficient efficacy, and the development of resistance. Unlike classical small molecule inhibitors that only block a single function or interaction of a protein involved in oncogenic signaling, proteolysis-targeting chimeras (PROTACs) degrade the entire protein, thus offering a potential paradigm shift. PROTACs are bivalent small molecules that recruit a target protein in proximity to an E3 ligase, promoting the transfer of ubiquitin, which marks the protein for proteasomal degradation. Because of their unique properties, PROTACs offer an attractive alternative as targeted therapeutics. The first PROTAC entered the clinic 5 years ago, and since then more than 30 have followed. In this review, we discuss the current compounds being investigated in the clinic, the key aspects of their design, and their potential for treating cancer.

Keyword(s): clinical trials, PROTACs, targeted protein degradation, ubiquitin E3 ligase
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2025-04-11
2025-06-14
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/content/journals/10.1146/annurev-cancerbio-061824-105806
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Development of PROTAC Degrader Drugs for Cancer
Annual Review of Cancer Biology 9, 119 (2025); https://doi.org/10.1146/annurev-cancerbio-061824-105806
/content/journals/10.1146/annurev-cancerbio-061824-105806
/content/journals/10.1146/annurev-cancerbio-061824-105806
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