Small‐Molecule PROTACS: New Approaches to Protein Degradation
Abstract
The current inhibitor‐based approach to therapeutics has inherent limitations owing to its occupancy‐based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off‐target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event‐driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small‐molecule‐based proteolysis‐targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes.
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PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner.
“Thus, PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [29]
PROTACs are bivalent small molecules containing a ligand that recognizes a target protein linked to another ligand that recruits a specific E3 ubiquitin ligase.
“PROTACs are bivalent small molecules containing a ligand that recognizes a target protein linked to another ligand that recruits a specific E3 ubiquitin ligase29,30.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [29]
PROTAC binding induces proximity-induced ubiquitination of the target protein and its subsequent degradation by proteasomes.
“PROTAC binding induces proximity-induced ubiquitination of the target protein and its subsequent degradation by proteasomes.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [29]
This increase is likely due to PROTACs' catalytical action to induce protein degradation in a sub-stoichiometric manner, and that their effect is not limited by equilibrium occupancy as are conventional inhibitors such as ABT263.
“This increase is likely due to PROTACs’ catalytical action to induce protein degradation in a sub-stoichiometric manner, and that their effect is not limited by equilibrium occupancy as are conventional inhibitors such as ABT263 (refs. 29,30).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [29]
Successful degradation by small molecule degraders requires induced heterodimerization between the E3 ubiquitin ligase and the target, resulting in the target's polyubiquitination and subsequent proteasomal degradation.
“Successful degradation requires induced heterodimerization between the E3 ligase and the target of interest, resulting in the target’s polyubiquitination and subsequent proteasomal degradation[8].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [8]
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- Authors
- Toure, M., & Crews, C. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2016-01-12
- Volume
- 55
- Issue
- 6
- Pages
- 1966-1973
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2237051895
- Cited by
- 674
- References
- 68
- Citations by year
- 2026: 54 · 2025: 69 · 2024: 81 · 2023: 59 · 2022: 82 · 2021: 71 · 2020: 82 · 2019: 66 · 2018: 40 · 2017: 46 · 2016: 24
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leukemia & Lymphoma Society
- NIH (R35A197589, R01AI084140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, protein degradation, cell quality control, off-target effects
- MeSH terms
- Proteins, Small Molecule Libraries, Proteolysis
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