ArticleJournal of medicinal chemistry2018
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 (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed, 158 citations in OpenAlex.
- Unique fluoroalkyl substituents: is there life after CFChemical science · 2026Review
- Recent advances of dual PROTACs for potential therapeutic applications.Molecular diversity · 2026Review
- Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).Cancer metastasis reviews · 2026Review
- Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review.Pharmaceutics · 2026Review
- Rescuing the Function of Missense-Mutated Tumor SuppressorbioRxiv : the preprint server for biology · 2026Article
- Metastable Protein-Protein Interactions as a Design Principle for PROTACs: Insights from the RIPK1-VHL System.JACS Au · 2026Article
- Dual FLT3/MAPK14 Proteolysis-Targeting Chimera (PROTAC) Induces Potent Acute Myeloid Leukemia Cell Death.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Branching beyond bifunctional linkers: synthesis of macrocyclic and trivalent PROTACs.Nature protocols · 2026Review
- PROTAC-Mediated Ternary Complex Stability with Ricin Toxin A: A Computational Perspective.ACS omega · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- Context Matters: E3 Ligase-Ligand Pairing Strategies for Optimized PROTAC Performance.Protein & cell · 2025Article
- Targeting Protein Tyrosine Phosphatases via PROteolysis-TArgeting Chimeras (PROTACs): Current Developments and Prospects.Molecules (Basel, Switzerland) · 2025Review
- Design, Optimization, and Development of RIPK1 Degraders with Improved Pharmacokinetic and Pharmacodynamic Properties.Journal of medicinal chemistry · 2025Article
- Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles.Journal of the American Chemical Society · 2025Article
- Stick it with VHL.Nature chemical biology · 2025Article
- Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes.Nature communications · 2025Article
- A Functional Assay for Mining Noninhibitory Enzyme Ligands from One Bead One Compound Libraries: Application to E3 Ubiquitin Ligases.Journal of the American Chemical Society · 2025Article
- E3Docker: a docking server for potential E3 binder discovery.Nucleic acids research · 2025Article
- Advancing Design Strategy of PROTACs for Cancer Therapy.MedComm · 2025Review
- A Perspective on the Strategic Application of Deconstruction-Reconstruction in Drug Discovery.Journal of medicinal chemistry · 2025Review
26 more citing papers are in PubMed but not listed here.
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9 authors at 1 institution in 1 country.
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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.
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