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Molecular Pharmacology

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Research ArticleArticle

CINPA1 Is an Inhibitor of Constitutive Androstane Receptor That Does Not Activate Pregnane X Receptor

Milu T Cherian, Wenwei Lin, Jing Wu and Taosheng Chen
Molecular Pharmacology May 2015, 87 (5) 878-889; DOI: https://doi.org/10.1124/mol.115.097782
Milu T Cherian
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Wenwei Lin
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Jing Wu
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Taosheng Chen
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Abstract

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug resistance. CAR inhibitors, in combination with existing chemotherapeutics, could therefore be used to attenuate multidrug resistance in cancers. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR, rendering them mechanistically counterproductive in tissues where both these xenobiotic receptors are present and active. We used a directed high-throughput screening approach, followed by subsequent mechanistic studies, to identify novel, potent, and specific small-molecule CAR inhibitors that do not activate PXR. We describe here one such inhibitor, CINPA1 (CAR inhibitor not PXR activator 1), capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM. CINPA1 1) is a specific xenobiotic receptor inhibitor and has no cytotoxic effects up to 30 µM; 2) inhibits CAR-mediated gene expression in primary human hepatocytes, where CAR is endogenously expressed; 3) does not alter the protein levels or subcellular localization of CAR; 4) increases corepressor and reduces coactivator interaction with the CAR ligand-binding domain in mammalian two-hybrid assays; and 5) disrupts CAR binding to the promoter regions of target genes in chromatin immunoprecipitation assays. CINPA1 could be used as a novel molecular tool for understanding CAR function.

Footnotes

    • Received January 8, 2015.
    • Accepted March 11, 2015.
  • This work was supported by the American Lebanese Syrian Associated Charities, St. Jude Children’s Research Hospital, and the National Institutes of Health (NIH) [Grants R01-GM086415, R01-GM110034, and P30-CA21765]. Human primary hepatocytes were obtained through the Liver Tissue and Cell Distribution System (Pittsburgh, PA), which is funded by NIH Contract N01-DK-7-0004/HHSN267200700004C.

  • dx.doi.org/10.1124/mol.115.097782.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (5)
Molecular Pharmacology
Vol. 87, Issue 5
1 May 2015
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Research ArticleArticle

CINPA1 Is a Novel and Unique CAR Inhibitor

Milu T Cherian, Wenwei Lin, Jing Wu and Taosheng Chen
Molecular Pharmacology May 1, 2015, 87 (5) 878-889; DOI: https://doi.org/10.1124/mol.115.097782

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Research ArticleArticle

CINPA1 Is a Novel and Unique CAR Inhibitor

Milu T Cherian, Wenwei Lin, Jing Wu and Taosheng Chen
Molecular Pharmacology May 1, 2015, 87 (5) 878-889; DOI: https://doi.org/10.1124/mol.115.097782
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