bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)
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Abstract
Significance: Intracellular proteins interact with each other to perform functions that are critical to normal and disease states. Attempts at altering pathological protein–protein interactions with traditional approaches have largely failed. Here, we explore an emerging approach we call “bioPROTACs”—engineered fusion proteins that consist of a target binding domain and an E3 ligase, an arrangement that results in the specific degradation of the therapeutic target. Our systematic study shows bioPROTAC design requirements are highly flexible in terms of both the binding domain and E3 ligase components. Resulting molecules can be used as powerful tools for uncovering biology, informing on the design of small molecule target degraders (e.g. PROTACs), and, if delivery issues can be addressed, potential therapeutics.
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The anti-GFP bioPROTAC platform has been used to generate GFP-degrading bioPROTACs based on various E3 ligases: CUL1 ligases β-TRCP, FBW7 and SKP2; CUL2 ligase VHL; CUL3 ligase SPOP; CUL5 ligases SOCS2 and ASB1; and U-box E3 ligase CHIP.
“The platform has been used to generate GFP-degrading bioPROTACs based on various E3 ligases: the CUL1 ligases β-TRCP, F-box and WD repeat domain-containing 7 (FBW7) and SKP2; the CUL2 ligase VHL; the CUL3 ligase speckle type BTB/POZ protein (SPOP); the CUL5 ligases suppressor of cytokine signalling 2 (SOCS2) and ankyrin repeat and SOCS box-containing 1 (ASB1); and the U-box E3 ligase CHIP.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [214]
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Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression
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Discovery of a Natural Ent-Kaurene Diterpenoid Oridonin as an E3 Ligase Recruiter for PROTACs
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The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents
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Degron-Based bioPROTACs for Controlling Signaling in CAR T Cells
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Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizersPreprint
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PROTAC: a revolutionary technology propelling small molecule drugs into the next golden age
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New PROTAC Designs for Targeted Protein Degradation in 2021–2025: Novel E3 Ligases and Pre-PROTACs
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Bivalent target-binding bioPROTACs induce potent degradation of oncogenic SHP2
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Genetic retargeting of E3 ligases to enhance CAR T cell therapy
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Small-Molecule Approaches to Target Transcription Factors
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TUBA1C: a new potential target of LncRNA EGFR-AS1 promotes gastric cancer progression
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Targeting UBE2C for degradation by bioPROTACs based on bacterial E3 ligase
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Systematic evolution of functional oligonucleotides for targeted protein degradation
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Proteolysis‐Targeting Chimera (PROTAC): A Revolutionary Tool for Chemical Biology Research
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Perspectives on the Development of First-in-Class Protein Degraders
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The chemical biology of ubiquitin
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Targeted protein and protein-condensate degradation in plant science research and crop breeding
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mRNA PROTACs: engineering PROTACs for high‐efficiency targeted protein degradation
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Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells
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Discovery of SOCS7 as a versatile E3 ligase for protein-based degraders
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The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events
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“100 The second domain typically consists of an E3 ubiquitin ligase, which adds ubiquitin to the target protein, marking it for degradation 97 (Fig.”
Molecular features defining the efficiency of bioPROTACs
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bioPROTACs establish RAS as a degradable target and provide novel RAS biology insightsPreprint
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- Authors
- Lim, S., Khoo, R., Peh, K. M., Teo, J., Chang, S. C., Ng, S., Beilhartz, G. L., Melnyk, R. A., Johannes, C. W., Brown, C. J., Lane, D. P., Henry, B., & Partridge, A. W.
- Affiliations
- MSD (Singapore) (SG)
- Pacific Translational Biomarkers, MSD International, Singapore 138665;
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Partridge, Anthony W.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-03-02
- Volume
- 117
- Issue
- 11
- Pages
- 5791-5800
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7084165
- OpenAlex
- W3010201122
- Cited by
- 170
- References
- 52
- Citations by year
- 2026: 30 · 2025: 38 · 2024: 35 · 2023: 26 · 2022: 18 · 2021: 15 · 2020: 8
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (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
- PROTACs, targeted protein degradation, proliferating cell nuclear antigen, DNA synthesis, cell cycle progression, oncology drug targets
- MeSH terms
- Binding Sites, Humans, Protein Binding, Recombinant Proteins, Protein Engineering, Proliferating Cell Nuclear Antigen, Ubiquitin-Protein Ligases, HEK293 Cells, Molecular Targeted Therapy, Proteolysis
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