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A Covalent Inhibitor for Glutathione S ‐Transferase Pi (GSTP 1‐1 ) in Human Cells
Author(s) -
Shishido Yuko,
Tomoike Fumiaki,
Kuwata Keiko,
Fujikawa Haruka,
Sekido Yoshitaka,
MurakamiTonami Yuko,
Kameda Tomoshi,
Abe Naoko,
Kimura Yasuaki,
Shuto Satoshi,
Abe Hiroshi
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800671
Subject(s) - glutathione , chemistry , gstp1 , sulfonyl , intracellular , conjugate , mechanism of action , glutathione s transferase , in vitro , covalent bond , biochemistry , cysteine , pharmacology , enzyme , stereochemistry , biology , organic chemistry , mathematical analysis , alkyl , mathematics
Glutathione S ‐transferase π (GSTP 1‐1 ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP 1‐1 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 GSTP 1‐1 both in vitro and in cellulo with a long duration of action.