ArticleJournal of medicinal chemistry2025
Impact of Linker Composition on VHL PROTAC Cell Permeability.
Article in Journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Pulse Programme Considerations for Quantitative NOE Analysis.Magnetic resonance in chemistry : MRC · 2026Article
- Delivering Degradation: Nanomedicine and Programmable Proximity Platforms for Targeted Protein Degradation.Pharmaceutics · 2026Review
- Solution Ensembles of Griselimycin Expand the Definition of Molecular Chameleonicity.Journal of medicinal chemistry · 2026Article
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Balancing Stability and Payload Release in Glutathione-Responsive PROTAC Prodrugs Targeting Prostate Cancer.JACS Au · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Article
- Conformational Dynamics in the Cell Membrane Interactions of Bispecific Targeted Degrader Therapeutics.Journal of medicinal chemistry · 2025Article
- Article
- Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs).Molecules (Basel, Switzerland) · 2025Article
- Dual functionality of MDM2 in PROTACs expands the horizons of targeted protein degradation.Biomarker research · 2025Review
- 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
- PROTAC Technology as a New Tool for Modern Pharmacotherapy.Molecules (Basel, Switzerland) · 2025Review
- Rational Design of PROTAC Linkers Featuring Ferrocene as a Molecular Hinge to Enable Dynamic Conformational Changes.Journal of the American Chemical Society · 2025Article
- Linker-Determined Folding and Hydrophobic Interactions Explain a Major Difference in PROTAC Cell Permeability.ACS medicinal chemistry letters · 2025Article
- PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation.Pharmaceutics · 2025Review
- Design, synthesis, and anti-inflammatory potential of PROTAC drug molecules based on fondaparinux sodium.Frontiers in bioengineering and biotechnology · 2025Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits of oral druggable space. We have designed a set of nine VHL PROTACs and found that the linker had a profound impact on passive cell permeability. Determination of the solution ensembles in a nonpolar solvent revealed that high permeability was correlated to the ability of the PROTACs to adopt folded conformations that have a low solvent accessible 3D polar surface area. Our results suggest that the design of cell permeable VHL PROTACs could focus on linkers that facilitate shielding of polar surface area in the VHL ligand in a nonpolar but not in a polar environment. In addition, we found that not only intramolecular hydrogen bonds, but also NH-π and π-π interactions contribute to the stabilization of low-polarity conformations, and thereby to high cell permeability.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.