The discovery and characterization of K ‐563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp

In the present study, we conducted high ‐throughput luciferase reporter screening to discover new Keap1/Nrf2 pathway inhibitors. From our screening, the novel compound K‐563 was isolated from the culture broth ofStreptomyces sp. 3728 ‐17 and was found to selectively inhibit the reporter activity of the Keap1/Nrf2 pathway. Furthermore, K‐563 inhibited the expression of Keap1/Nrf2 pathway downstream proteins, GSH synthesis and ROS resistance through the suppression of the Keap1/Nrf2 pathway downstream gene expression. AbstractKeap1/Nrf2 pathway regulates the antioxidant stress response, detoxification response, and energy metabolism. Previous reports found that aberrant Keap1/Nrf2 pathway activation due to Kelch ‐like ECH‐associated protein 1 (Keap1) mutations or Nuclear factor E2‐related factor 2 (Nrf2) mutations induced resistance of cancer cells to chemotherapy and accelerated cell growth via the supply of nutrients. Therefore, Keap1/Nrf2 pathway activation is associated with a poor prognosis in ma ny cancers. These previous findings suggested that inhibition of Keap1/Nrf2 pathway could be a target for anti‐cancer therapies. To discover a small‐molecule Keap1/Nrf2 pathway inhibitor, we conducted high‐throughput screening in Keap1 mutant human lung cancer A549 cells using a transcriptiona l reporter assay. Through this screening, we identified the novel Keap1/Nrf2 pathway inhibitor K‐563, which was isolated from actinomyceteStreptomyces sp. K ‐563 supp...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research