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Mol Pharmacol. 2007 Apr;71(4):1140-7. Epub 2007 Jan 17.

Structure-based identification of novel human gamma-glutamylcysteine synthetase inhibitors.

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1
Department 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.

PMID:
17229871
DOI:
10.1124/mol.106.024778
[Indexed for MEDLINE]
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