|
|||||
|
|
A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP1-1) in Human Cells |
|
| Authors: | Dr. Yuko Shishido Dr. Fumiaki Tomoike Dr. Keiko Kuwata Haruka Fujikawa Prof. Dr. Yoshitaka Sekido Dr. Yuko Murakami-Tonami Dr. Tomoshi Kameda Dr. Naoko Abe Dr. Yasuaki Kimura Prof. Dr. Satoshi Shuto Prof. Dr. Hiroshi Abe |
| Affiliation: | 1. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602 Japan;2. Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602 Japan;3. Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602 Japan;4. Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681 Japan;5. Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681 Japan Juntendo University, Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan;6. Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7, Aomi, Ko-to-ku, Tokyo, 135-0064 Japan;7. Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo, Hokkaido, 060-0812 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. |
| Keywords: | antitumor agents covalent inhibitors glutathione S-transferase irreversible inhibitors sulfonyl fluoride |