| Project/Area Number |
22K15246
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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 47010:Pharmaceutical chemistry and drug development sciences-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) |
2022-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | KRAS / RAS / 分子標的薬 / 抗がん剤 / 細胞膜透過性ペプチド / 人工タンパク質 / がん / RAS阻害剤 |
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| Outline of Research at the Start |
本研究で取り組むのは以下の3つの事項である。①本剤の合成展開：100種類以上の誘導体を合成する。②他抗がん剤との併用効果の検証：既存の抗がん剤との併用によって、マウスモデルでの腫瘍の退縮を目指す。③がん病態を忠実に再現するマウスモデルでの評価：例えば患者由来移植モデル（PDX）などで本剤を評価することで、臨床応用に繋がるデータを取得する。
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| Outline of Final Research Achievements |
RAS is the most popular cancer gene that is mutated to the active form in about 30% of cancers, and the development of Ras inhibitors has been underway around the world for about 40 years. The G12C mutant inhibitor sotorasib was approved in 2021, but no treatment for Ras mutants other than G12C has yet been approved. The principal investigator has been working on developing Ras inhibitors using artificial proteins since 2018, and in 2020 developed a new Ras inhibitor that can inhibit the non-G12C mutant Ras. In this study, we synthesized derivatives based on this inhibitor and evaluated their activity. As a result, we developed a novel Ras inhibitor X that exhibits strong antitumor effects in cultured cell models and tumor-bearing mouse models.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で開発した新規Ras阻害剤Xは細胞内に侵入し活性型Rasを強く阻害することができる。担がんマウスモデルでは80％を超える高い腫瘍退縮率を示す。さらに、Ｘは血中安定性が高く、毒性も低いため、創薬展開が可能なシーズである。よってXは、G12C以外のRas変異を標的とする新しい治療法へと発展する可能性がある。
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