Proteolysis‐targeting chimeras in drug development: A safety perspective
Open accessAbstract
Proteolysis‐targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit. As the first‐generation of proteolysis‐targeting chimeras have now entered clinical trials for oncology indications, it is timely to consider the theoretical safety risks inherent with this modality which include off‐target degradation, intracellular accumulation of natural substrates for the E3 ligases used in the ubiquitin proteasome system, proteasome saturation by ubiquitinated proteins, and liabilities associated with the “hook effect” of proteolysis‐targeting chimeras This review describes in vitro and non‐clinical in vivo data that provide mechanistic insight of these safety risks and approaches being used to mitigate these risks in the next generation of proteolysis‐targeting chimera molecules to extend therapeutic applications beyond life‐threatening diseases.
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An off-target effect can arise from neomorphic interactions with neosubstrates of an E3 ligase if the E3 ligase ligand used to generate the PROTAC or the PROTAC itself can bind the neosubstrates.
“An off-target effect can also arise from the neomorphic interactions with neosubstrates of an E3 ligase if the E3 ligase ligand used to generate the PROTAC or the PROTAC itself can bind the neosubstrates [206].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [206]
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- Authors
- Moreau, K., Coen, M., Zhang, A. X., Pachl, F., Castaldi, M. P., Dahl, G., Boyd, H., Scott, C., & Newham, P.
- Affiliations
- Oncology Safety, Clinical Pharmacology and Safety Sciences R&D AstraZeneca Cambridge UK
- AstraZeneca (United Kingdom) (GB)
- AstraZeneca (United States) (US)
- Structure, Biophysics and Fragment‐Based Lead Generation, Discovery Sciences, R&D AstraZeneca Gothenburg Sweden
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2020-02-25
- Volume
- 177
- Issue
- 8
- Pages
- 1709-1718
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC7070175
- OpenAlex
- W3004874245
- Cited by
- 229
- References
- 61
- Citations by year
- 2026: 34 · 2025: 46 · 2024: 44 · 2023: 44 · 2022: 28 · 2021: 20 · 2020: 11 · 2019: 1
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion)
- 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, drug safety, E3 ubiquitin ligase, hook effect, protein degradation, anticancer drug development, nonclinical safety assessment
- MeSH terms
- Chimera, Pharmaceutical Preparations, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Proteolysis
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