Targeted protein degradation: from mechanisms to clinic
Abstract
Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases - the principal waste disposal machines of a cell - and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.
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Of 18 PROTACs currently in clinical trials, 13 utilize CRL4 CRBN as the recruited ligase.
“indeed, of the 18 PROtAcs currently in clinical trials 13 utilize cRl4 cRBN as the recruited ligase (tsai et al. 2024).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Tsai et al. 2024
The vast majority (>70%) of molecular glue degraders currently in use or being evaluated in clinical trials target IKZF1/IKZF3.
“the vast majority (>70%) of molecular glue degraders currently in use, or being evaluated in clinical trials, target two proteins iKZF1/iKZF3 (tsai et al. 2024).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as tsai et al. 2024
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Self-citation
- Authors
- Tsai, J. M., Nowak, R. P., Ebert, B. L., & Fischer, E. S.
- Affiliations
- Broad Institute (US)
- University of Bonn (DE)
- Harvard University (US)
- Corresponding author
- Ebert, Benjamin L.
- Fischer, Eric S.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2024-04-29
- Volume
- 25
- Issue
- 9
- Pages
- 740-757
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- OpenAlex
- W4396230754
- Cited by
- 438
- References
- 36
- Citations by year
- 2026: 198 · 2025: 187 · 2024: 52 · 2022: 1
- FWCI
- 17.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- targeted protein degradation, PROTACs, molecular glues, E3 ubiquitin ligase, ubiquitination, proteasomal degradation, bifunctional degraders, small-molecule degraders, clinical trials, drug discovery
- MeSH terms
- Animals, Humans, Proteins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Ubiquitination, Proteolysis
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