Received for publication March 21, 2006.
Revised January 16, 2007.
Accepted for publication January 17, 2007.

Structure-based identification of novel classes of human -glutamylcysteine synthetase inhibitors active in deleting glutathione in tumor cells

Abstract

Glutathione depletion represents an potentially important strategy to sensitize tumors to cytotoxic drugs. L-buthionine-(R,S)-sulfoximine (L-BSO) has been studied in both pre-clinical and early clinical trials, but limitation on its access and potency has led to a search for alternatives. Using a 3D molecular model of human the major subunit of the rate-limiting GSH synthetic enzyme -glutamylcysteine synthetase (-GCSH), we virtually screened the NCI chemical database to identify compounds that could bind to and potentially inhibit -GCSH. We identified 51 test chemicals, all with structures very distinct from BSO. We subjected these compounds to biological assays meausuring -GCSH 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 -GCSH with novel chemical structures.

Key words: Structure-activity relationships and modeling, Prediction of structure-function/proteomics, Glutathione, Oxidative stress, Resistance