Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
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E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for ‘proteolysis-targeting chimeras’). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.
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CM11 specifically depleted the long isoform of VHL, VHL30, within 4 h at 10 nM concentration.
“The most active compound, CM11, specifically depleted the long isoform of VHL, VHL30, within 4 h at 10 nM concentration, providing an intriguing tool for research on isoform specific functions of VHL.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [95]
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Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
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Self-citationHypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets
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PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics
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Self-citationTrivalent PROTACs enhance protein degradation via combined avidity and cooperativity
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Self-citationE3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points
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Proteolysis‐targeting chimeras in drug development: A safety perspective
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<i>In Silico</i> Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application
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RNA‐PROTACs: Degraders of RNA‐Binding Proteins
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Harnessing the Power of Proteolysis for Targeted Protein Inactivation
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Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader
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E3 ligase ligand chemistries: from building blocks to protein degraders
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PROTACs– a game-changing technology
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Homo-PROTACs for the Chemical Knockdown of Cereblon
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Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs
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Targeted protein degradation and the enzymology of degraders
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Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
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Bivalent Ligands for Protein Degradation in Drug Discovery
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Redox signaling at the crossroads of human health and disease
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Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
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PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies
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Mechanistic and Structural Features of PROTAC Ternary Complexes
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Self-citationPROTAC-mediated crosstalk between E3 ligases
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Bifunctional chemical probes inducing protein–protein interactions
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Self-citationDesign and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader
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Self-citationExploring the target scope of KEAP1 E3 ligase-based PROTACs
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Advances in targeted degradation of endogenous proteins
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Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer
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Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
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PROTAC: A promising technology for cancer treatment
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Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
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Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy
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Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival
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Development of selective small molecule MDM2 degraders based on nutlin
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Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs
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Assays and Technologies for Developing Proteolysis Targeting Chimera Degraders
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Novel approaches for the rational design of PROTAC linkers
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PROTACs: A novel strategy for cancer drug discovery and development
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Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods
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Targeting androgen receptor degradation with PROTACs from bench to bedside
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Transforming targeted cancer therapy with PROTACs: A forward-looking perspective
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Self-citationTargeted protein degradation in cancers: Orthodox PROTACs and beyond
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Proteolysis targeting chimeras (PROTACs) for epigenetics research
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Recent Advances in PROTAC-Based Antiviral Strategies
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Self-citationRecent advances in targeted protein degraders as potential therapeutic agents
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- Authors
- Maniaci, C., Hughes, S. J., Testa, A., Chen, W., Lamont, D. J., Rocha, S., Alessi, D. R., Romeo, R., & Ciulli, A.
- Affiliations
- University of Dundee (GB)
- University of Messina (IT)
- Corresponding author
- Ciulli, Alessio
- ORCID
- Venue
- Nature Communications
- Published
- 2017-10-10
- Volume
- 8
- Issue
- 1
- Pages
- 830-830
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5635026
- OpenAlex
- W2761240402
- Cited by
- 245
- References
- 75
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 21 · 2023: 36 · 2022: 37 · 2021: 27 · 2020: 37 · 2019: 37 · 2018: 12 · 2017: 1
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Wellcome Trust (100476, 100476/Z/12/Z)
- Cancer Research UK (C99667/A12918, 12918)
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Medical Research Council (MC_UU_12016, MC_UU_12016/2)
- FP7 Ideas: European Research Council (311460)
- 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, VHL E3 ubiquitin ligase, ligand-induced dimerization, proteasomal degradation, isoform selectivity, ubiquitin-proteasome system, chemical probes
- MeSH terms
- Humans, Ligands, Dimerization, Ubiquitin, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries, Proteolysis
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