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 γ-glutamylcysteine synthetase (γ-GCSH), 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 γ-GCSH. We identified 51 test chemicals, all with structures very distinct from l-BSO. We subjected these compounds to biological assays measuring γ-GCSH inhibition and glutathione (GSH) depletion. Among 10 novel γ -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 γ-GCSH with novel chemical structures.
Footnotes
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This work was supported by Canadian Institute of Health Research via operating grants (to G.B. and J.H.W.) and by the Réseau de recherche sur le cancer, Fonds de la recherche en santé du Québec.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.024778.
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ABBREVIATIONS: GSH, glutathione; MRP1, multidrug resistance-related protein 1; l-BSO, l-buthionine-(R,S)-sulfoximine; γ-GCSH, γ-glutamylcysteine synthetase; NCI, National Cancer Institute; DMSO, dimethyl sulfoxide.
- Received March 21, 2006.
- Accepted January 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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