Glutathione S-transferase (GST) is a phase II drug metabolizing-enzyme and GSTs present in the cells are classified into multiple subtypes (GSTA1-1, GSTM2-2, GSTP1-1 etc.) depending on the difference in structure and intracellular localization. GST catalyzes the conjugation of GSH to a wide range of hydrophobic and electrophilic compounds. As a result, the GS-conjugated compounds are extruded from the cell through multidrug resistance proteins (MRP) (Fig. 1A). Several subtypes of GSTs are highly expressed in several cancers and can result in resistance to anticancer agents. Thus, the GST inhibitor is a promising approach for cancer treatment. Although GST inhibitors have been developed, multiple- or high- dose administration is necessary to maintain continuous inhibition of GST because they compete with GSH, which is present in the cells at high concentrations. Thus, we planned to develop GST covalent inhibitors. This strategy could bring about a prolonged residence time, as well as sustained and strong inhibition. We designed several covalent inhibitors of GST based on GSH structure, and successfully identified one promising compound. In this presentation, we will report on the new covalent inhibitor having sulfonyl fluoride (SF) group as the reactive functional group named as GS-ESF (Fig. 1B). LC-MS/MS and X-ray structure analyses clarified that GS-ESF reacted with Tyr108 of GSTP1-1. Furthermore, based on MD calculation, we propose a dynamic reaction mechanism of GS-ESF.

Development of glutathione S-transferase (GST) covalent inhibitor

255th National Meeting (2018)

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