A screening of novel anti-tumor compounds targeting p53 degradation

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17646
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Tokuyama Shinji 大阪大学, 医学系研究科, 招へい教員 (00804890)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 大腸癌 / p53

Outline of Final Research Achievements

We constructed a unique sensitive high-throughput screening system using p53 protein degradation as an index. Using this system, 10000 small molecule compound libraries were screened and 68 hit compounds were identified. The effect on the endogenous p53 protein was evaluated and narrowed down to 7 compounds. Two of these compounds have the same skeleton and have not been reported to have any effect on p53. These compounds did not cause DNA damage to colorectal cancer cell lines, while stabilizing p53 protein by inhibiting ubiquitination. In addition, the pull-down assay and thermal shift assay did not show inhibition of p53-MDM2 binding, and it was clarified that stabilization by degradation inhibition was achieved by a mechanism different from that of MDM2 inhibitors.

Free Research Field

大腸癌

Academic Significance and Societal Importance of the Research Achievements

本邦において大腸癌は罹患数・死亡数ともに上位に入る悪性腫瘍であり、進行再発病変に対する薬物加療は新たな薬剤の開発により延長しているとはいえ根治に至ることは困難でありさらなる分子メカニズムに基づいた治療の開発が望まれている。Pp53タンパク質を活性化するMDM2阻害剤が今まで報告されていたが血液毒性が問題となっており、新たな機序によるp53活性化剤の開発が期待されている。本研究で同定した化合物がその候補であり、またスクリーニング系を用いることでさらなる化合物ライブラリでの評価が可能となる。