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Updated: Jul 17, 2026
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Structure-based identification of novel human gamma-glutamylcysteine synthetase inhibitors
David Hamilton1, Jian Hui Wu, Gerald Batist
1Department of Oncology, McGill University, Montreal Centre for Experimental Therapeutics in Cancer and Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Abstract:
Glutathione depletion represents a potentially important strategy to sensitize tumors to cytotoxic drugs. l-Buthionine-(R,S)-sulfoximine (l-BSO) has been studied in both preclinical and early clinical trials, but limitation on its access has led to a search for alternatives. Using a 3D molecular model of human gamma-glutamylcysteine synthetase (gamma-GCS(H)), the major subunit of the rate-limiting GSH synthetic enzyme, we virtually screened the National Cancer Institute chemical database to identify compounds that could bind to and potentially inhibit gamma-GCS(H). We identified 51 test chemicals, all with structures very distinct from l-BSO. We subjected these compounds to biological assays measuring gamma-GCS(H) inhibition and glutathione (GSH) depletion. Among 10 novel gamma -GCS inhibitors identified, 4 compounds depleted glutathione in cells, and 2 with related structures sensitized tumor cells to melphalan treatment. This work validates the use of model-based database mining and identified inhibitors of gamma-GCS(H) with novel chemical structures.
Insights
Researchers identified novel compounds that inhibit glutathione synthesis, potentially sensitizing tumors to chemotherapy. This approach offers alternatives to l-BSO for cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Glutathione depletion is a strategy to enhance tumor sensitivity to cytotoxic drugs.
- l-Buthionine-(R,S)-sulfoximine (l-BSO) is a known inhibitor but has access limitations, necessitating alternative compounds.
- Human gamma-glutamylcysteine synthetase (gamma-GCS(H)) is the rate-limiting enzyme in glutathione synthesis.
Purpose of the Study:
- To identify novel inhibitors of gamma-glutamylcysteine synthetase (gamma-GCS(H)) through virtual screening.
- To discover alternative compounds for glutathione depletion in cancer therapy.
Main Methods:
- Utilized a 3D molecular model of human gamma-GCS(H) for virtual screening of the National Cancer Institute chemical database.
- Identified 51 potential inhibitor candidates with structures distinct from l-BSO.
- Performed biological assays to measure gamma-GCS(H) inhibition and glutathione (GSH) depletion in cells.
Main Results:
- Identified 10 novel gamma-GCS inhibitors.
- Four of these compounds effectively depleted glutathione in cells.
- Two structurally related compounds demonstrated the ability to sensitize tumor cells to melphalan treatment.
Conclusions:
- Model-based database mining is a valid approach for identifying enzyme inhibitors.
- Novel chemical structures targeting gamma-GCS(H) were identified.
- These findings offer potential new therapeutic strategies for cancer treatment by enhancing drug sensitivity through glutathione depletion.
