2019 Fiscal Year Final Research Report
Development of gamma-tubulin specific inhibitor
| Project/Area Number |
17K01949
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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 |
Biomolecular chemistry
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| Research Institution | Okayama University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | γ-チューブリン / 分子設計 / 構造活性相関 |
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| Outline of Final Research Achievements |
Inhibitors of α,β-tubulin polymerization or depolymerization are cytotoxic against tumor cells. On the other hand, γ-tubulin is forms the γ-tubulin ring complex (γ-TuRC), which is the starting point of α,β-tubulin polymerization in cells. In light of this phenomenon, γ-tubulin is an attractive target protein for the development of novel types of anticancer drugs. Previously, we have developed gatastatin, which does not affect α,β-tubulin polymerization and specifically inhibits γ-tubulin functions including GTP binding.
In this research, we attempted to structure-activity relationship study of gatastatin. As a result, O6-propargyl gatastatin, named "gatastatin G2", showed potent cytotoxicity. And also, this derivative both inhibits γ-tubulin-dependent nucleation and induces abnormal spindle formation, suggesting that gatastatin G2 is a more potent γ-tubulin-specific inhibitor than gatastatin and is a useful tool for investigating γ-tubulin function in cells.
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| Free Research Field |
天然物合成化学
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| Academic Significance and Societal Importance of the Research Achievements |
これまで抗がん剤の標的タンパク質であり，微小管を形成するα,β-チューブリンに関する研究は多くあったが，微小管形成の重合起点となるγ-チューブリンの機能については不明な点が多かった．γ-チューブリン特異的阻害剤は微小管形成の元から絶つことができるので，新たな創薬ターゲットや生命現象解明のツールとして期待できる．本研究ではこれまでに報告例のない強力なγ-チューブリン特異的阻害剤である「ガタスタチンG2」を開発した．今後ガタスタチンG2を用いることにより，新たな生命現象の解明につながる可能性が高く，その波及効果は大きい．
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