A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer.
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.
Department of Chemistry, The Scripps Research Institute , 10550, North Torrey Pines, La Jolla, California 92037, United States.
Michael J
MJ
Bollong
Department of Chemistry, The Scripps Research Institute , 10550, North Torrey Pines, La Jolla, California 92037, United States.
Hwayoung
H
Yun
California Institute for Biomedical Research , 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
Lance
L
Sherwood
California Institute for Biomedical Research , 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
Ashley K
AK
Woods
Department of Chemistry, The Scripps Research Institute , 10550, North Torrey Pines, La Jolla, California 92037, United States.|California Institute for Biomedical Research , 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
Luke L
LL
Lairson
Department of Chemistry, The Scripps Research Institute , 10550, North Torrey Pines, La Jolla, California 92037, United States.|California Institute for Biomedical Research , 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
Peter G
PG
Schultz
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009369:Neoplasms / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D054852:Small Molecule Libraries; C058214:2-amino-5-ethylidene-1-methylimidazol-4-one