ArticleBioorganic & medicinal chemistry letters2021
Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.
Article in Bioorganic & medicinal chemistry letters, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.Molecular neurobiology · 2023Pooled it
- Multilayer modulation of the proteasome: new strategies for neuroprotection.Frontiers in molecular neuroscience · 2026Article
- Development of dihydroquinazoline compounds as novel therapeutics against Naegleria fowleri.Bioorganic & medicinal chemistry letters · 2025Article
- Unveiling the Potential of a New β-Cyclodextrin-Suxibuzone Conjugate in Proteasome Regulation.ChemMedChem · 2025Article
- Recent Advancements in 20S Proteasome Enhancement: Degradation of Undruggable Targets.ACS medicinal chemistry letters · 2025Review
- Sex and Genotype Affect Mouse Hippocampal Gene Expression in Response to Blast-Induced Traumatic Brain Injury.Molecular neurobiology · 2025Article
- Tandem Synthesis of Tetrahydropyrroloquinazolines and Related Polyannular Scaffolds.The Journal of organic chemistry · 2025Article
- Peptidomimetics Activating the Proteasome: A New Perspective for Parkinson's Treatment.Journal of medicinal chemistry · 2025Article
- Article
- Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome.ACS chemical biology · 2025Article
- Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives.Genes & diseases · 2024Review
- 20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.iScience · 2024Article
- Rpt5-Derived Analogs Stimulate Human Proteasome Activity in Cells and Degrade Proteins Forming Toxic Aggregates in Age-Related Diseases.International journal of molecular sciences · 2024Article
- Proteasome Activators and Ageing: Restoring Proteostasis Using Small Molecules.Sub-cellular biochemistry · 2024Review
- Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.Frontiers in cell and developmental biology · 2024Review
- Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators.ACS omega · 2023Article
- Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer's-like pathology in mouse and fly APP overexpression models.Science advances · 2022Article
- Peptidomimetics Based onBiomolecules · 2022Article
- Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.Biomedicines · 2022Article
- Advances in Proteasome Enhancement by Small Molecules.Biomolecules · 2021Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.
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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 Socratic graph.