Protein degraders enter the clinic — a new approach to cancer therapy
Open accessAbstract
Heterobifunctional protein degraders, such as PROteolysis TArgeting Chimera (PROTAC) protein degraders, constitute a novel therapeutic modality that harnesses the cell's natural protein-degradation machinery - that is, the ubiquitin-proteasome system - to selectively target proteins involved in disease pathogenesis for elimination. Protein degraders have several potential advantages over small-molecule inhibitors that have traditionally been used for cancer treatment, including their event-driven (rather than occupancy-driven) pharmacology, which permits sub-stoichiometric drug concentrations for activity, their capacity to act iteratively and target multiple copies of a protein of interest, and their potential to target nonenzymatic proteins that were previously considered 'undruggable'. Following numerous innovations in protein degrader design and rigorous evaluation in preclinical models, protein degraders entered clinical testing in 2019. Currently, 18 protein degraders are in phase I or phase I/II clinical trials that involve patients with various tumour types, with a phase III trial of one initiated in 2022. The first safety, efficacy and pharmacokinetic data from these studies are now materializing and, although considerably more evidence is needed, protein degraders are showing promising activity as cancer therapies. Herein, we review advances in protein degrader development, the preclinical research that supported their entry into clinical studies, the available data for protein degraders in patients and future directions for this new class of drugs.
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In contrast to conventional small-molecule inhibitors, PROTAC employs an "event-driven" degradation process rather than an "occupancy-driven" binding mechanism, rendering PROTAC highly efficient and capable of rapidly degrading intracellular target proteins, including drug-resistant mutants.
“In contrast to conventional small-molecule inhibitors, PROTAC employs an “event-driven” degradation process rather than an “occupancy-driven” binding mechanism, rendering PROTAC highly efficient and capable of rapidly degrading intracellular target proteins, including drug-resistant mutants.482”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [482]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Chirnomas, D., Hornberger, K. R., & Crews, C. M.
- Affiliations
- Arvinas (United States) (US)
- Yale University (US)
- Corresponding author
- Chirnomas, Deborah
- Hornberger, Keith R.
- Crews, Craig M.
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2023-02-13
- Volume
- 20
- Issue
- 4
- Pages
- 265-278
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- PMC
- PMC11698446
- OpenAlex
- W4320480893
- Cited by
- 658
- References
- 135
- Citations by year
- 2026: 147 · 2025: 238 · 2024: 210 · 2023: 63
- FWCI
- 17.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R35CA197589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, ubiquitin-proteasome system, targeted protein degradation, cancer therapy, clinical trials, undruggable proteins, drug development, antitumour activity
- MeSH terms
- Humans, Neoplasms, Proteins, Proteolysis
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