Deubiquitinase that inhibits degradation of oncogenic fusion proteins and its implication to cancer therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02777
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Naito Mikihiko 東京大学, 大学院薬学系研究科(薬学部), 特任教授 (00198011)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 融合タンパク質 / 脱ユビキチン化酵素 / タンパク質分解 / PROTAC / SNIPER

Outline of Final Research Achievements

Cancer cells often express oncogenic fusion genes generated by chromosomal translocations. Such fusion genes are not present in normal cells and play crucial role in oncogenesis. Therefore, the encoded fusion proteins are promising targets for cancer therapy. In this study, we searched for deubiquitinating enzymes required for the expression of oncogenic fusion proteins. We also developed novel PROTAC/SNIPER compounds that induce the degradation of oncogenic fusion proteins such as FGFR3-TACC3, EML4-ALK, NPM-ALK and FLT3-ITD.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

がん特異的融合タンパク質の一部は細胞のがん化に決定的な役割を果たしており、がんの治療標的分子として重要である。本研究で開発した、FGFR3-TACC3、EML4-ALK、 NPM-ALK、FLT3-ITDを分解する新規PROTAC/SNIPER化合物は、これらの融合タンパク質を発現するがん細胞に対する特異的な抗がん剤を開発するためのリード化合物となる可能性が考えられる。