Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction
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E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extraordinarily challenging as modulation of E3 ligase activities requires the targeting of protein-protein interactions. Using rational design, we have generated the first small molecule targeting the von Hippel-Lindau protein (VHL), the substrate recognition subunit of an E3 ligase, and an important target in cancer, chronic anemia, and ischemia. We have also obtained the crystal structure of VHL bound to our most potent inhibitor, confirming that the compound mimics the binding mode of the transcription factor HIF-1α, a substrate of VHL. These results have the potential to guide future development of improved lead compounds as therapeutics for the treatment of chronic anemia and ischemia.
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The majority of degraders recruit the CRL4crbn or CRL2vhl E3 ligases to ubiquitinate a protein of interest.
“The majority of degraders recruit the CUL4-RBX1-DDB1-CRBN (CRL4crbn) (Ito et al., 2010; Kronke et al., 2014; Winter et al., 2015), or CUL2-RBX1-ElonginB-ElonginC-VHL (CRL2vhl) (Buckley et al., 2012; Galdeano et al., 2014) E3 ligases to ubiquitinate a POI.”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Buckley et al., 2012
The discovery of small-molecule mimetics of the HIF1α peptide opened the door to the rational design of PROTACs based wholly on small molecular structures - for example, the first PROTACs based on the bromodomain protein inhibitor JQ1 that recruited VHL to degrade bromodomain-containing protein 4 (BRD4).
“The discovery of small-molecule mimetics of the HIF1α peptide20,21 opened the door to the rational design of PROTACs based wholly on small molecular structures — for example, the first PROTACs based on the bromodomain protein inhibitor JQ1 that recruited VHL to degrade bromodomain-containing protein 4 (BRD4)22,23.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [21]
A peptidic ligand molecule with an IC50 value of 4.1 μM for VHL binding at the HIF1α binding site was developed, and could be improved to sub-micromolar affinity.
“This hydroxyproline residue was the starting point for a peptidic ligand molecule with an IC50 value of 4.1 µM for VHL binding at the HIF1α binding site [89], which could be improved to sub-micromolar affinity [90].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [89]
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Self-citation
- Authors
- Buckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M.
- Affiliations
- Yale University (US)
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
- University of Cambridge (GB)
- Corresponding author
- Ciulli, Alessio
- Crews, Craig M.
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-02-27
- Volume
- 134
- Issue
- 10
- Pages
- 4465-4468
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC3448299
- OpenAlex
- W1994344724
- Cited by
- 569
- References
- 28
- Citations by year
- 2026: 49 · 2025: 78 · 2024: 86 · 2023: 43 · 2022: 57 · 2021: 52 · 2020: 44 · 2019: 42 · 2018: 24 · 2017: 24 · 2016: 16 · 2015: 17 · 2014: 18 · 2013: 12 · 2012: 7
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American Chemical Society (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- U.S. Department of Defense
- Biotechnology and Biological Sciences Research Council
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- von Hippel-Lindau protein, E3 ubiquitin ligase, small molecule inhibitors, protein-protein interaction inhibition, crystal structure, rational drug design, chronic anemia, ischemia, cancer
- MeSH terms
- Humans, Ligands, Models, Molecular, Magnetic Resonance Spectroscopy, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Small Molecule Libraries
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