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A small molecule inhibits deregulated NRF2 transcriptional activity in cancer

Academic Article
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Overview

related to degree

  • Bollong, Michael Joseph, Ph.D. in Chemical Biology, Scripps Research 2010 - 2016

authors

  • Bollong, Michael Joseph
  • Yun, H.
  • Sherwood, L.
  • Woods, A. K.
  • Lairson, Luke
  • Schultz, Peter

publication date

  • October 2015

journal

  • ACS Chemical Biology  Journal

abstract

  • NRF2 serves as the master regulator of oxidative stress resistance in mammalian cells. Although NRF2 activation decreases tumorigenic events in normal cells, accumulating evidence suggests that cancers have broadly selected for NRF2-activating mutations to promote anabolic growth and chemoresistance. Small molecules which inhibit NRF2 activity may therefore offer promise as an alternative anticancer treatment in NRF2 dependent cancers. We have used a high throughput screen to identify small molecules which decrease NRF2 transcriptional activity at antioxidant response element sites. One such molecule, termed AEM1, is capable of broadly decreasing the expression of NRF2 controlled genes, sensitizing A549 cells to various chemotherapeutic agents, and inhibiting the growth of A549 cells in vitro and in vivo. Profiling of multiple cell lines for their responsiveness to AEM1 revealed that AEM1's activities are restricted to cell lines harboring mutations which render NRF2 constitutively active.

subject areas

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles
  • Male
  • Mice
  • Mice, Nude
  • NF-E2-Related Factor 2
  • Neoplasms
  • Oxidative Stress
  • Small Molecule Libraries
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Identity

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/acschembio.5b00448

PubMed ID

  • 26270491
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Additional Document Info

start page

  • 2193

end page

  • 2198

volume

  • 10

issue

  • 10

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