Abstract
Nrf2-Keap1 system is a biological defense mechanism in response to various stressors. An inhibitor for Keap1-Nrf2 interaction to activate Nrf2 is expected as a novel target for drug discovery in oxidative stress-related disorders. However, Nrf2 is accumulated in many types of cancer and its expression is induced during the course of drug resistance, which is mediated by phosphorylated p62 (p-p62), an autophagy-related protein that forms a complex with Keap1. We performed a high-throughput screening for Keap1-Nrf2 inhibitory activity toward around 160,000 compounds, and identified a hit compound #1 that has a benzoindole skeleton. #1 inhibited Keap1-Nrf2 interaction with a submicromolar IC50 value, suggesting that #1 would be a novel lead-compound for Nrf2 activator. Moreover, we also found #2, a unique compound that more strongly inhibits Keap1-p-p62 interaction than Keap1-Nrf2 interaction. #2 has an acetonyl side-chain on the naphthalene skeleton and the treatment of #2 suppressed proliferation and reduced tolerance to cisplatin or sorafenib in HCC. This result showed that #2 was expected as an Nrf2 suppressor which should be developed for the treatment of malignancy progression and chemoresistance.
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