Gtg

Another enzyme that is overexpressed in several tumors, including ovarian, colon, pancreas, and non-small lung cell cancers, is the cytosolic glutathione-S-transferase of the p class (GST-p). The active site of this enzyme contains a tyrosine residue that deprotonates the mercapto group of glutathione in order to increase its nucleophilicity and to allow its reaction with electrophilic toxic metabolites (Fig. 11.2).

The mustard prodrug TLK-286 contains a modified glutathione framework linked to an inactive phosphoramide mustard. The presence of a sulfone group in the linker was designed to enhance the acidity of the a-proton and thus facilitate a p-elimination reaction triggered by the basicity of the deprotonated tyrosine hydroxyl. The negative charge in the liberated phosphoramidate assists the intramolecular nucleophilic displacement reaction that leads to the alkylating aziridi-nium species (Fig. 11.3). Although the activation of TLK-286 can occur spontaneously, the enzyme facilitates the kinetics of the process. TLK-286 is under Phase III testing for non-small cell lung and ovarian cancers.2

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