Identification of narciclasine as a novel NRF2 inhibitor.

Cancer genome sequencing studies have identified somatic mutations in the KEAP1/NRF2 pathway. In an effort to identify novel NRF2 small molecule inhibitor(s), we have screened a natural compound library comprising 1330 chemicals in A549-ARE-GFP-luciferase cells and identified that narciclasine significantly inhibits NRF2-dependent luciferase activity. Narciclasine suppressed the expression of NRF2 and NRF2 target genes, caused significant oxidative stress, and sensitized cisplatin-mediated apoptosis in A549 cells.