Development of a cell membrane permeable protein that inhibits oncogene RAS proteins

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15246
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Gifu University
• 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)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: KRAS / RAS / 分子標的薬

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.

Free Research Field

がん創薬

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。