Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Caitlin LynchMenghang Xia

Abstract

The nuclear receptor, estrogen-related receptor alpha (ERRα; NR3B1), plays a pivotal role in energy homeostasis. Its expression fluctuates with the demands of energy production in various tissues. When paired with the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the PGC/ERR pathway regulates a host of genes that participate in metabolic signaling networks and in mitochondrial oxidative respiration. Unregulated overexpression of ERRα is found in many cancer cells, implicating a role in cancer progression and other metabolism-related diseases. Using high throughput screening assays, we screened the Tox21 10K compound library in stably transfected HEK293 cells containing either the ERRα-reporter or the reporter plus PGC-1α expression plasmid. We identified two groups of antagonists that were potent inhibitors of ERRα activity and/or the PGC/ERR pathway: nine antineoplastic agents and thirteen pesticides. Results were confirmed using gene expression studies. These findings suggest a novel mechanism of action on bioenergetics for five of the nine antineoplastic drugs. Nine of the thirteen pesticides, which have not been investigated previously for ERRα disrupting activity, were classified as such. In conclus...Continue Reading

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Citations

Mar 4, 2020·International Journal of Molecular Sciences·Madhulika TripathiBrijesh Kumar Singh
Aug 23, 2020·International Journal of Molecular Sciences·Luca FrattaruoloAnna Rita Cappello
Jun 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yasunari Matsuzaka, Yoshihiro Uesawa
Jan 25, 2022·Journal of Biomolecular Structure & Dynamics·André FischerMartin Smieško

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Methods Mentioned

BETA
acetylation
Assay
PCR

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