Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation Journal Article


Authors: Liu, H. Y.; Tuckett, A. Z.; Fennell, M.; Garippa, R.; Zakrzewski, J. L.
Article Title: Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation
Abstract: 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. © 2017, Springer Science+Business Media, LLC, part of Springer Nature.
Keywords: drug development; reactive oxygen species; high-throughput screening; cancer; nrf2; small molecule inhibitor
Journal Title: Investigational New Drugs
Volume: 36
Issue: 4
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2018-08-01
Start Page: 590
End Page: 600
Language: English
DOI: 10.1007/s10637-017-0557-6
PROVIDER: scopus
PUBMED: 29297149
DOI/URL:
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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MSK Authors
  1. Andrea Tuckett
    15 Tuckett
  2. Ralph James Garippa
    14 Garippa
  3. Myles Ashley Fennell
    18 Fennell
  4. Hsiu Yu Liu
    2 Liu