ArticleInvestigational new drugs2018
Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation.
Article in Investigational new drugs, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Modulators of the Nrf2 Signaling Pathway Enhance the Cytotoxic Effect of Standard Chemotherapeutic Drugs on Organoids of Metastatic Colorectal Cancer.Bulletin of experimental biology and medicine · 2024Article
- TAZ upregulates MIR-224 to inhibit oxidative stress response in multiple myeloma.Cancer reports (Hoboken, N.J.) · 2023Article
- Modulation of Cellular Redox Parameters for Improving Therapeutic Responses in Multiple Myeloma.Antioxidants (Basel, Switzerland) · 2022Review
- A review for cell-based screening methods in drug discovery.Biophysics reports · 2021Article
- Development of targeted therapy of NRF2Cellular signalling · 2021Review
- Role of NRF2 in Lung Cancer.Cells · 2021Review
- Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway.Cell death & disease · 2021Article
- Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells.Frontiers in cell and developmental biology · 2021Article
- Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases.Cancers · 2020Review
- Brusatol: A potential anti-tumor quassinoid fromChinese herbal medicines · 2020Review
- Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2.International journal of molecular sciences · 2020Review
- Nrf2 in cancers: A double-edged sword.Cancer medicine · 2019Review
- Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP.Journal of clinical pathology · 2019Article
- Potential Applications of NRF2 Inhibitors in Cancer Therapy.Oxidative medicine and cellular longevity · 2019Review
- Targeting CDC7 improves sensitivity to chemotherapy of esophageal squamous cell carcinoma.OncoTargets and therapy · 2019Article
- NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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.
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