Structure-based identification of novel human gamma-glutamylcysteine synthetase inhibitors.
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.
Hamilton
David
D
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.
Wu
Jian Hui
JH
Batist
Gerald
G
D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione