Development of RET inhibitor based on the interaction between the kinase protein and inhibitor

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16817
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Nakaoku Takashi 国立研究開発法人国立がん研究センター, 研究所, 研究員 (20779491)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: キナーゼ阻害剤 / RET / がんゲノム医療

Outline of Final Research Achievements

In this study, we aim to select inhibitors against mutant RET by screening and to obtain knowledge for designing kinase inhibitors that are less susceptible to drug resistance mutations. We identified and reported new resistance mutations from specimens acquired drug resistance. Based on the list of mutations collected, we introduced the mutations into proteins and cell models to obtain drug sensitivity information. We also succeeded in obtaining the co-crystal structure of the purified protein and the inhibitor. Based on the crystal structure information, we performed molecular simulation to understand binding stability. We confirmed the correlation between the experimental data and the susceptibility data obtained from the molecular simulation.

Free Research Field

ゲノム生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、キナーゼに生じる変異を題材に、患者由来のゲノム情報と実験データをもとに分子シミュレーション手法を組み合わせ、薬剤結合変化をコンピューター上でシミュレートすることで、感受性の推定モデルの構築を行った。本研究にて構築するのは、従来の実験科学主導型の研究アプローチとコンピューター手法を融合させることで両分野の双方向性を促し、新たな機能解析方法としてコンピュター駆動による阻害剤開発方法を目指す点で学術的意義を有している。また、患者個人の遺伝子情報に臨床的意義を与えると同時に適正な薬剤選択を可能にし、我が国のがんゲノム医療の推進への寄与が期待できる。