The chemistry and biology of inhibitors and pro-drugs targeted to glutathione S-transferases.

The cytosolic glutathione S-transferases are a family of structurally homologous enzymes with multiple functions, including xenobiotic detoxification, clearance of oxidative stress products, and modulation of cell proliferation and apoptosis signaling pathways. This wide-ranging functional repertoire leads to several possible therapeutic uses for isoform-specific GST inhibitors. These inhibitors may be used, in principle, to modulate tumor cell drug resistance, as sensitizers to therapeutically directed oxidative stress, to enhance cell proliferation and to augment anti-malarial drugs. With increasing knowledge of GST structural and function, rational design strategies and mechanism-based inhibitors have been exploited successfully. However, design of isoform specificity remains a significant challenge in GST inhibitor development. Strategies for further inhibitor design and their possible limitations, along with potential therapeutic uses, are summarized.