ArticleACS medicinal chemistry letters2022
Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties.
Article in ACS medicinal chemistry letters, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.Journal of advanced research · 2026Article
- Diastereomeric Branched-Ester dBET1 Analogs Exhibit Conformation-Dependent Differences in Passive Membrane Permeability.Journal of medicinal chemistry · 2026Article
- Hydrophobic tagging: A promising paradigm for targeted protein degradation.Cell insight · 2026Review
- Evolution of proteolysis-targeting chimeras (PROTAC) technology to overcome challenges of antimicrobial resistance.npj antimicrobials and resistance · 2025Review
- Advancements in Proteolysis Targeting Chimeras for Targeted Therapeutic Strategies in Alzheimer's Disease.Molecular neurobiology · 2025Review
- Advancements in PROTAC-based therapies for neurodegenerative diseases.Future medicinal chemistry · 2025Review
- Article
- PDE1B and PDE10A as novel targets for schizophrenia: from molecular design and synthesis to therapeutic promise.Frontiers in pharmacology · 2025Review
- Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions.Bioconjugate chemistry · 2024Review
- The neuropathobiology of multiple sclerosis.Nature reviews. Neuroscience · 2024Review
- Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40.Structure (London, England : 1993) · 2023Article
- Central Nervous System Targeted Protein Degraders.Biomolecules · 2023Review
- Emerging Strategies in Proteolysis-Targeting Chimeras (PROTACs): Highlights from 2022.International journal of molecular sciences · 2023Review
- Ubiquitin-modifying enzymes in Huntington's disease.Frontiers in molecular biosciences · 2023Review
Corrections and comments
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The onset of neurodegenerative disorders (NDs), such as Alzheimer's disease, is associated with the accumulation of aggregates of misfolded proteins. We previously showed that chemical knockdown of ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into the central nervous system, where NDs are located. Here, we document the conversion of one of our PROTACs into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic degrons. This conversion decreases the molecular weight and the number of hydrogen bond donors/acceptors. All the developed HyTs lowered the level of mutant huntingtin, an aggregation-prone protein, with potency comparable to that of the parent PROTAC. Through IAM chromatography analysis and in vivo brain penetration assay of the HyTs, we discovered a brain-permeable HyT. Our results and mechanistic analysis indicate that conversion of protein degraders into HyTs could be a useful approach to improve their drug-like properties.
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Registered trials
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