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

摘要: Keap1/Nrf2 pathway regulates the antioxidant stress response, detoxification and energy metabolism. Previous reports found that aberrant activation due to Kelch-like ECH-associated protein 1 (Keap1) mutations or Nuclear factor E2-related 2 (Nrf2) induced resistance of cancer cells chemotherapy accelerated cell growth via supply nutrients. Therefore, is associated with a poor prognosis in many cancers. These previous findings suggested inhibition could be target for anti-cancer therapies. To discover small-molecule inhibitor, we conducted high-throughput screening Keap1 mutant human lung A549 using transcriptional reporter assay. Through this screening, identified novel inhibitor K-563, which was isolated from actinomycete Streptomyces sp. K-563 suppressed expression downstream genes protein, suppression GSH production, activated reactive oxygen species production cells. also inhibited other Keap1- Nrf2-mutated Furthermore, exerted anti-proliferative activities these mutated vitro analyses showed able inhibit by inhibition. synergistic combinational effects chemotherapeutic agents. An vivo study mice xenotransplanted further explore therapeutic potential revealed it tumors. may lead compound development as an agent.