ArticleScientific reports2019
Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Phytochemical study ofPharmaceutical biology · 2026Article
- EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge.Nature communications · 2026Article
- Potent Inducers of Paraptosis through Electronic Tuning of Hemicyanine Electrophiles.Journal of the American Chemical Society · 2025Article
- Dynamic networks connect the USP14 active site region with the proteasome interaction surface.Protein science : a publication of the Protein Society · 2025Article
- Regulation of adipocyte differentiation and lipid metabolism by novel synthetic chromenes exploring anti-obesity and broader therapeutic potential.Scientific reports · 2025Article
- Tractable Quinolone Hydrazides Exhibiting Sub-Micromolar and Broad Spectrum Antitrypanosomal Activities.ChemMedChem · 2024Article
- Electrophilic Compounds in the Human Diet and Their Role in the Induction of the Transcription Factor NRF2.International journal of molecular sciences · 2024Review
- A diastereoselective three-component reaction for the assembly of succinimide and isatin hybrid molecules with potent anticancer activities.Molecular diversity · 2023Article
- Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer.Journal of experimental & clinical cancer research : CR · 2022Article
- Comprehensive Target Screening and Cellular Profiling of the Cancer-Active Compound b-AP15 Indicate Abrogation of Protein Homeostasis and Organelle Dysfunction as the Primary Mechanism of Action.Frontiers in oncology · 2022Article
- Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System.Biomolecules · 2021Article
- Potential Cancer- and Alzheimer's Disease-Targeting Phosphodiesterase Inhibitors fromACS omega · 2021Article
- Dienone Compounds: Targets and Pharmacological Responses.Journal of medicinal chemistry · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
16 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (~20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.
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