ArticleJournal of medicinal chemistry2022
Linker-Dependent Folding Rationalizes PROTAC Cell Permeability.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
55 citing papers in PubMed.
- Context matters in PROTAC design: navigating the trade-off between degradation and developability.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Harnessing the ubiquitin-proteasome system: advances and challenges of PROTACs in breast cancer.Molecular biology reports · 2026Review
- Limiting Trial-and-Error: Linker-Based 2D Descriptor Analysis to Support Very Early Proteolysis-Targeting Chimeras Design.ChemMedChem · 2026Article
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- Solution Ensembles of Griselimycin Expand the Definition of Molecular Chameleonicity.Journal of medicinal chemistry · 2026Article
- COMPASS: A Computational Pipeline to Identify Linkers Predicting Ubiquitinable PROTAC-Induced Ternary Complexes.ChemMedChem · 2026Article
- Balancing Stability and Payload Release in Glutathione-Responsive PROTAC Prodrugs Targeting Prostate Cancer.JACS Au · 2026Article
- Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review.Pharmaceutics · 2026Review
- Assays for Measuring the Cell Permeability of Proteolysis-Targeting Chimeras (PROTACs): Performance, Correlations, Applicability and Recommendations.Molecular pharmaceutics · 2026Article
- Pyridine-containing antitumor agents: structure-oriented medicinal chemistry, structure-activity relationships, and ADMET liabilities.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Proteolysis-targeting chimera (PROTAC) in cancer: design principles and applications on "undruggable" targets.Biomarker research · 2026Review
- Coacervate-Mediated Lysosome-Targeting Antibody Delivery for Protein Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors.ACS medicinal chemistry letters · 2026Article
- Article
- Diastereomeric Branched-Ester dBET1 Analogs Exhibit Conformation-Dependent Differences in Passive Membrane Permeability.Journal of medicinal chemistry · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- Article
- Targeted protein degradation dismantles undruggable targets to reverse immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
- Conformational Dynamics in the Cell Membrane Interactions of Bispecific Targeted Degrader Therapeutics.Journal of medicinal chemistry · 2025Article
Corrections and comments
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, the outer limits of oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently to gain insights into the origin of the differences in cell permeability displayed by three flexible cereblon PROTACs having closely related structures. Both methods revealed that the propensity of the PROTACs to adopt folded conformations with a low solvent-accessible 3D polar surface area in an apolar environment is correlated to high cell permeability. The chemical nature and the flexibility of the linker were essential for the PROTACs to populate folded conformations stabilized by intramolecular hydrogen bonds, π-π interactions, and van der Waals interactions. We conclude that MD simulations may be used for the prospective ranking of cell permeability in the design of cereblon PROTACs.
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Registered trials
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.