Development of an Nrf2 inhibitor for the treatment of Nrf2-addicted cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16512
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Baird Liam 東北大学, 医学系研究科, 助教 (90724914)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Keap1-Nrf2

Outline of Final Research Achievements

Activation of the KEAP-NRF2 pathway is observed in approximately 30% of human lung tumours, where it is associated with a poor prognosis and reduced overall survival for patients. Despite the fact that NRF2 is a validated driver of aggressive cancer growth, the complete lack of approved drugs which can target oncogenic NRF2 signaling means that there is an urgent clinical need to identify compounds which display efficacy against NRF2-dependent tumours. In this project, I developed a novel assay to identify compounds which could selectively kill tumour cells with high levels of NRF2 activity. Using this approach, I identified two different classes of compounds, geldanamycin-derived HSP90 inhibitors, and the DNA damaging agent mitomycin C, which both displayed NRF2-dependent toxicity.

Free Research Field

Medical Biochemistry

Academic Significance and Societal Importance of the Research Achievements

As there are no approved drugs which can be used to treat patients with NRF2-dependent tumours, there is an urgent unmet clinical need to identify such drugs. In this project, I identified the chemotherapy drug mitomycin C to be an ideal candidate for drug repositioning to NRF2-dependent tumours.