Development of chemoresistance-overcoming agent targeting p62-Keap1-Nrf2 axis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16322
• 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: Osaka Medical and Pharmaceutical University (2021); Keio University (2019-2020)
• Principal Investigator: Yasuda Daisuke 大阪医科薬科大学, 薬学部, 助教 (40736097)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: Nrf2 / p62 / 抗がん剤耐性 / Keap1

Outline of Final Research Achievements

While Nrf2 is important protein for biological defense, it is known to be involved in drug resistance in certain types of cancer cells. In this study, we designed, synthesized and evaluated compounds that enhance sensitivity to anticancer drugs in cancer cells with aberrant activation of Nrf2 due to overexpression of p62. Derivatives of K67 obtained by screening were synthesized and their activities were evaluated. As a result, we found two compounds that showed effective potentiation of anticancer drug activity in hepatocellular carcinoma and lung cancer cells, respectively. one of the compounds showed Nrf2 activation in cells that did not overexpress p62, indicating that it is a unique compound that specifically enhances anticancer drug resistance in cancer cells.

Free Research Field

創薬化学、有機化学、ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

抗がん剤耐性の出現は治療上・社会上の重大な問題である。本研究ではNrf2の異常活性化により既存の抗がん剤への耐性を獲得した癌細胞株に対して、それ自身は細胞生存率に影響せず、抗がん剤への感受性を増強させるユニークな創薬シーズを見出した。この成果は、Nrf2抑制剤が新規な癌治療戦略として有望であることを示すとともに、悪性度の高い癌細胞を低コストな既存の抗がん剤を主体とした処理で対処可能にするという画期的な成果である。