| Project/Area Number |
17K08366
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | University of Shizuoka |
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Principal Investigator |
Ogo Naohisa 静岡県立大学, 薬学研究院, 講師 (20501307)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | デュアル作用薬 / プロドラッグ / MD解析 / 構造最適化 / がん細胞選択的 / GGT / 次世代抗がん剤 / システイン誘導体 / 細胞増殖阻害 / デュアル作用 / 構造活性相関 / 抗がん / KSP / がん微小環境 / SMDC |
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| Outline of Final Research Achievements |
To create novel kinesin spindle protein (KSP) inhibitors highly selective for cancer cells, we optimized the amino acid moiety of S-Trityl-L-cysteine derivative 1 using in silico modeling. Molecular docking and MD simulation were performed to investigate the binding mode. Consistent with the results of SARs, we found the amino group plays an important role to stabilize the interaction. Based on these findings and the structure of GSH a substrate of γ-glutamyltransferase (GGT), we designed the prodrug, N-γ-Glutamylated derivative 2 which could be hydrolyzed by GGT to produce 1. GGT is overexpressed on the cell membrane of various cancer cells. The KSP ATPase inhibitory activity of 2 was lower than 1 and LCMS analysis indicated 2 was converted to 1 only in the presence of GGT. Cytotoxicity of 2 was significantly attenuated in GGT-knockdown A549 cells. Those results suggest that 2 could be a promising prodrug that selectively inhibits the proliferation of GGT-expressing cancer cells.
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| Academic Significance and Societal Importance of the Research Achievements |
独自開発したKSP阻害システイン誘導体を基に、その阻害様式を共結晶構造やMD計算等駆使して明らかとしつつ、それらの情報を活かして今までにない次世代抗がん剤開発のためのリード化合物（プロドラッグ）を創製できたことはオリジナリティの高い研究成果であり、更にKSP自身の生物学的意義に関する研究の深化にもつながると考えられる。またこれらの研究成果は学会・論文発表を通じて社会に公表することにより、抗がん剤開発をはじめとした科学リテラシー向上にも貢献するものと考えられる。
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