ArticleChembiochem : a European journal of chemical biology2023
Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis.
Article in Chembiochem : a European journal of chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 6 citations in OpenAlex.
- Tipping the balance: NRF2's dual role in ferroptotic fate.Oncogenesis · 2026Review
- Cross-ancestry proteome-wide Mendelian randomization prioritizes 12 plasma protein candidates for breast cancer risk.medRxiv : the preprint server for health sciences · 2026Article
- Coptidis Rhizoma Alkaloids Alleviate Acetaminophen-Induced Liver Injury by Regulating GSH Metabolism and the TNF Signaling Pathway.Antioxidants (Basel, Switzerland) · 2026Article
- Multi-Pathway Study for Oxaliplatin Resistance Reduction.Current issues in molecular biology · 2025Review
- Glutathione dynamics in subcellular compartments and implications for drug development.Current opinion in chemical biology · 2024Review
- Glutathione-Dependent Pathways in Cancer Cells.International journal of molecular sciences · 2024Review
- Investigation of the regulatory mechanisms of Guiqi Yimu Powder on dairy cow fatty liver cells using a multi-omics approach.Frontiers in veterinary science · 2024Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibition of their cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive ligand, EN25, that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, and leads to inhibition of GCL activity. This interaction also leads to reduced cellular GSH levels and impaired cell viability in ARID1A-deficient cancer cells, which are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit GSH synthesis in vulnerable cancer cell types.
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Registered trials
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