Projects per year
Abstract
Hypoxia-inducible factor-1α (HIF-1α) constitutes the principal mediator of cellular adaptation to hypoxia in humans. The HIF-1α protein level and activity are tightly regulated by the ubiquitin E3 ligase von Hippel-Lindau (VHL). Here, we performed a structure-guided and bioactivity-driven design of new VHL inhibitors. Our iterative and combinatorial strategy focused on chemical variability at the phenylene unit and encompassed further points of diversity. The exploitation of tailored phenylene fragments and the stereoselective installation of the benzylic methyl group provided potent VHL ligands. Three high-resolution structures of VHL-ligand complexes were determined, and bioactive conformations of these ligands were explored. The most potent inhibitor (30) exhibited dissociation constants lower than 40 nM, independently determined by fluorescence polarization and surface plasmon resonance and an enhanced cellular potency, as evidenced by its superior ability to induce HIF-1α transcriptional activity. Our work is anticipated to inspire future efforts toward HIF-1α stabilizers and new ligands for proteolysis-targeting chimera (PROTAC) degraders.
Original language | English |
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Pages (from-to) | 12776-12811 |
Number of pages | 36 |
Journal | Journal of Medicinal Chemistry |
Volume | 66 |
Issue number | 18 |
Early online date | 14 Sept 2023 |
DOIs | |
Publication status | Published - 28 Sept 2023 |
Keywords
- Aromatic compounds
- Inhibitors
- Ligands
- Peptides and proteins
- Screening assays
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Dive into the research topics of 'Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel-Lindau E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1α Stabilizers'. Together they form a unique fingerprint.-
EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/20 → 30/04/25
Project: Research
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DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/13 → 30/04/18
Project: Research
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A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research