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Updated: Feb 1, 2026
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP1-1 ) in Human Cells
Yuko Shishido1,2, Fumiaki Tomoike3, Keiko Kuwata4
1Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan.
Abstract:
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.
Insights
New chloronitrobenzene sulfonyl fluoride (CNBSF) inhibitors effectively target glutathione S-transferase π (GSTP1-1) in cancer. These compounds demonstrate improved cellular permeability and sustained inhibition of intracellular GSTP1-1, offering a promising therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Glutathione S-transferase π (GSTP1-1) is overexpressed in various cancers, contributing to drug resistance.
- GSTP1-1 is a significant therapeutic target for cancer treatment, necessitating effective inhibitors.
Purpose of the Study:
- To develop novel irreversible inhibitors of GSTP1-1 with enhanced cellular permeability.
- To elucidate the mechanism of action for new GSTP1-1 inhibitors.
Main Methods:
- Synthesis of chloronitrobenzene sulfonyl fluoride (CNBSF) derivatives.
- In vitro and in cellulo assays to evaluate GSTP1-1 inhibition.
- Mechanistic studies involving glutathione (GSH) conjugation and reaction with GSTP1-1.
Main Results:
- New CNBSF inhibitors demonstrated irreversible inhibition of GSTP1-1 both in vitro and in cellulo.
- The inhibitors exhibit improved cellular permeability compared to previous compounds.
- The mechanism involves GSH conjugation followed by reaction with Tyr108 of GSTP1-1.
Conclusions:
- CNBSF derivatives represent a promising class of irreversible GSTP1-1 inhibitors for cancer therapy.
- Enhanced cellular permeability and sustained inhibition offer potential for overcoming drug resistance.
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