A Covalent Inhibitor for Glutathione S‐Transferase Pi (GSTP1‐1) in Human Cells

Glutathione S‐transferase π (GSTP1‐1) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP1‐1 is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS‐ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST. We have now developed new irreversible inhibitors by introducing sulfonyl fluoride (SF) into chloronitrobenzene (CNB). The mechanism of action was revealed to be that CNBSF first reacts with glutathione (GSH) through an aromatic substitution in the cell, then the sulfonyl group on the GSH conjugate with CNBSF reacts with Tyr108 of GST to form a sulfonyl ester bond. Our new inhibitor irreversible inhibited GSTP1‐1 both in vitro and in cellulo with a long duration of action. Development of G‐site inhibitors: We have developed benzene sulfonyl fluoride (BSF)‐type covalent GST inhibitors with cell membrane permeability. LC‐MS/MS analysis confirmed that the inhibitors form a covalent bond with GST in human cells.