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Structure-Based Identification of Novel Human -Glutamylcysteine Synthetase Inhibitors

Departments of Oncology, Pharmacology and Therapeutics, 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

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 -glutamylcysteine synthetase (-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 -GCS_H. We identified 51 test chemicals, all with structures very distinct from L-BSO. We subjected these compounds to biological assays measuring -GCS_H inhibition and glutathione (GSH) depletion. Among 10 novel -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 -GCS_H with novel chemical structures.

Address correspondence to: Dr. Gerald Batist, Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, QC, Canada, H3T 1E2. E-mail: gbatist{at}onc.jgh.mcgill.ca