ArticleACS medicinal chemistry letters2025
Linker-Determined Folding and Hydrophobic Interactions Explain a Major Difference in PROTAC Cell Permeability.
Article in ACS medicinal chemistry letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities.Drug delivery · 2026Review
- Cell Surface Deazaflavin-Diazirine Energy-Transfer (DarT) Photoproximity Labeling Using Antibody Conjugates.Bioconjugate chemistry · 2026Article
- Solution Ensembles of Griselimycin Expand the Definition of Molecular Chameleonicity.Journal of medicinal chemistry · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors.ACS medicinal chemistry letters · 2026Article
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- PROTAC-Splitter: a machine learning framework for automated identification of PROTAC substructures.Journal of cheminformatics · 2026Article
- Diastereomeric Branched-Ester dBET1 Analogs Exhibit Conformation-Dependent Differences in Passive Membrane Permeability.Journal of medicinal chemistry · 2026Article
- Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs).Molecules (Basel, Switzerland) · 2025Article
- Linker Methylation as a Strategy to Enhance PROTAC Oral Bioavailability: Insights from Molecular Properties and Conformational Analysis.Journal of medicinal chemistry · 2025Article
- TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- New Multiparameter Index Is a Strong Predictor of Oral Bioavailability for Heterobifunctional Degraders.ACS medicinal chemistry letters · 2025Article
- PROTAC Technology as a New Tool for Modern Pharmacotherapy.Molecules (Basel, Switzerland) · 2025Review
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ability to adopt folded conformations that have a low solvent-accessible 3D polar surface area has been found to be important for PROTACs to display a high passive cell permeability. We have studied two VHL PROTACs that differ only by the replacement of two methylene groups in the linker by oxygen atoms but that displayed vast differences in their cell permeability. MD simulations and NMR spectroscopy revealed an unexpected, environment-dependent conformational behavior for the low-permeability PROTAC that has an alkyl linker. Hydrophobic interactions enforced extended and polar conformations for this PROTAC in nonpolar media, explaining its low cell permeability. In water, hydrophobic collapse around the linker led to folded and less polar conformations. In contrast, the highly permeable PROTAC having a PEG linker adopted conformations of similar shapes and polarities in polar and nonpolar environments.
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Registered trials
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