| Project/Area Number |
17K15479
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Drug development chemistry
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| Research Institution | Nagoya University |
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Principal Investigator |
Tomoike Fumiaki 名古屋大学, 物質科学国際研究センター, 助教 (70708586)
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| Research Collaborator |
SHISHIDO Yuko
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | タンパク質科学 / 阻害剤 / GST / 抗がん剤 / 不可逆阻害 / 共有結合性阻害剤 / グルタチオン / 酵素 / 結晶構造解析 / グルタチオン S トランスフェラーゼ |
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| Outline of Final Research Achievements |
Glutathione S-transferase (GST) plays the important role in cellular detoxification. Unfortunately, this mechanism contributes to the resistance of anti-cancer drug. Because of this, GST inhibition is required for cancer therapy. Some competitive inhibitors towards GST has been reported. However, cellular glutathione reduces the effect of the inhibitors. To avoid this, we developed covalent inhibitor towards GST. As first generation, we developed GS-ESF by introducing surfonyl fluoride into glutathione. Though GS-ESF inhibited GST in vitro, its low cellular permeability inhibited the inhibition of cellular GST. As second generation, we developed CNBSF by replacing one of two nitro groups in CDNB, a major substrate of GST. By biochemical and cellular assays, we confirmed that CNBSF inhibited GST both in vitro and in cell.
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| Academic Significance and Societal Importance of the Research Achievements |
グルタチオン S-トランスフェラーゼ(GST)は細胞の抗ガン剤耐性にかかわる酵素である。本研究では、細胞内のGSTと共有結合を形成して阻害するという新しいコンセプトのもと、新規の阻害剤を開発した。阻害に必要な濃度はまだ高いものの、共有結合を形成して阻害するというコンセプトは証明できたため、本阻害剤の誘導体を検討することにより、より効果的な阻害剤の実現とそれによるがん治療の前進が期待できる。
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