Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α
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By design: Novel small-molecule inhibitors of the interaction between the von Hippel–Lindau ligase (VHL) and its molecular target HIF1α, a transcription factor involved in oxygen sensing, have been developed and studied. The most potent inhibitor binds with an IC50 value of 0.9 μM and is thus the first sub-micromolar inhibitor of the VHL–HIF1α interaction.
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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 [20]
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 [90]
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References 34 · Cited by 302
- Authors
- Buckley, D. L., Gustafson, J. L., Van Molle, I., Roth, A. G., Tae, H. S., Gareiss, P. C., Jorgensen, W. L., Ciulli, A., & Crews, C. M.
- Affiliations
- Yale University (US)
- University of Cambridge (GB)
- Corresponding author
- Crews, Craig M.
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2012-10-12
- Volume
- 51
- Issue
- 46
- Pages
- 11463-11467
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC3519281
- OpenAlex
- W2003632864
- Cited by
- 302
- References
- 34
- Citations by year
- 2026: 20 · 2025: 34 · 2024: 29 · 2023: 28 · 2022: 35 · 2021: 29 · 2020: 26 · 2019: 22 · 2018: 16 · 2017: 21 · 2016: 12 · 2015: 9 · 2014: 16 · 2013: 5
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/G023123/1)
- National Institute of General Medical Sciences (GM 032136, R01GM032136, F32GM10052101, F32GM100521)
- National Institute of Allergy and Infectious Diseases (R01AI084140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- VHL, HIF-1α, E3 ubiquitin ligase, protein-protein interaction inhibitors, small molecule inhibitors, oxygen sensing, transcription factors
- MeSH terms
- Enzyme Inhibitors, Humans, Models, Molecular, Drug Design, Crystallography, X-Ray, Inhibitory Concentration 50, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Interaction Maps
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