Oxidative stress and cellular response mechanisms such as NRF2-mediated
antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of
reactive oxygen species is a hallmark of many
cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for
cancer therapy by preferentially targeting
cancer cells for induction of oxidative stress. We found that the NRF2 inhibitor
brusatol triggered increased oxidative stress while compromising viability and proliferation of
multiple myeloma cells. Using a repurposing approach we discovered that the Cdc7/CDK9 inhibitor
PHA-767491 is also a potent inhibitor of NRF2 transcriptional activity. The molecule was identified by high throughput screening of a library of about 5900
drug-like molecules. Screening assays included two cell-based assays using HepG2
hepatocellular carcinoma cells: a) A NRF2 nuclear translocation assay, and b) A NRF2
luciferase reporter assay. Validation assays were performed in
multiple myeloma cells and included detection of mitochondrial
superoxide levels and MTS assays. We found that
PHA-767491 treatment of
multiple myeloma cells was associated with inhibition of nuclear translocation of NRF2, increased mitochondrial
superoxide levels and inhibition of cell growth. Our findings suggest that
PHA-767491 is a promising
drug candidate for
cancer therapy with NRF2 inhibitory potency contributing to its anti-
cancer properties.