Soares, Pedro, Gadd, Morgan S, Frost, Julianty ORCID: 0000-0001-8209-2575, Galdeano, Carles, Ellis, Lucy, Epemolu, Ola, Rocha, Sonia, Read, Kevin D and Ciulli, Alessio
(2018)
Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2<i>S</i>,4<i>R</i>)-1-((<i>S</i>)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyI)-4-hydroxy-<i>N</i>-(4-(4-methylthiazol-5-yl)benzyppyrrolidine-2-carboxamide (VH298).
JOURNAL OF MEDICINAL CHEMISTRY, 61 (2).
pp. 599-618.
Abstract
The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.
Item Type: | Article |
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Uncontrolled Keywords: | Animals, Humans, Mice, Cyclopropanes, Pyrrolidines, Thiazoles, Enzyme Inhibitors, Drug Evaluation, Preclinical, Drug Stability, Cell Membrane Permeability, Structure-Activity Relationship, Female, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Chemistry Techniques, Synthetic |
Depositing User: | Symplectic Admin |
Date Deposited: | 10 Jan 2018 10:18 |
Last Modified: | 14 Oct 2023 22:28 |
DOI: | 10.1021/acs.jmedchem.7b00675 |
Open Access URL: | http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7... |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3015780 |