Development of a new anticancer drug using a protein that has high affinity and specifically binds to mutant Ras
| Project/Area Number |
19K16828
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Gifu University |
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Principal Investigator |
Honda Ryo 岐阜大学, 大学院連合創薬医療情報研究科, 准教授 (00820143)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | RAS / 抗がん剤 / 分子標的薬 / 細胞膜透過性タンパク質 / RAS阻害剤 |
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| Outline of Research at the Start |
RAS遺伝子の変異は全がんの約20％に認められるが，変異型Rasタンパク質を阻害する分子標的薬はいまだにない．変異型Rasの分子表面には低分子化合物が結合できるポケット（鍵穴）がなく，従来の低分子創薬の手法では変異型Rasに高親和性かつ特異的に結合する薬剤を開発することは極めて困難である．そこで本研究では変異型Rasに高親和性かつ特異的に結合するタンパク質Xに着目し，これを細胞内に導入することで変異型Rasを阻害する手法を開発する．
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| Outline of Final Research Achievements |
KRAS is one of the most important targets in cancer treatment. However, it has been considered as an undruggable target with conventional small molecules and antibodies. In this study, by synthesizing 51 fusion recombinant proteins. we succeeded in identifying a novel KRAS inhibitor with a micromolar inhibitory activity in cultured cell lines. The proteins consist of a RAS-binding protein with a cell-permeable peptide and thereby penetrates through the cell membrane. The best inhibitor shows an inhibitory activity comparable to that of existing small molecule RAS inhibitors, and thus can be considered as a promising lead for the development of new anticancer drugs (Cell Chemical Biology 2021, WO/2022/039026).
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で開発したRAS阻害剤の最大の特色は、従来の創薬分子や次世代医薬品のどれとも異なる「細胞膜透過性タンパク質」であるという点である。このため本剤は、分子量が1万Daを超える高分子量タンパク質であるにも関わらず、細胞膜を透過し、細胞内に存在するRASに到達し阻害することが可能である。このようなアプローチはKRASのみならず、他のundruggable targetにも応用することが期待できる。
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Report
(4 results)
Research Products
(3 results)
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[Journal Article] Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains2021
Author(s)
Nomura, T.K., Heishima, K., Sugito, N., Sugawara, R., Ueda, H., Akao, Y. and Honda, R.
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Journal Title
Cell Chemical Biology
Volume: -
Issue: 11
Pages: 1581-1589.e6
DOI
Related Report
Peer Reviewed
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