CINPA1 is an inhibitor of constitutive androstane receptor that does not activate pregnane X receptor

Molecular Pharmacology
Milu T CherianTaosheng Chen

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 inh...Continue Reading

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Citations

May 17, 2015·Expert Opinion on Drug Metabolism & Toxicology·Milu T CherianTaosheng Chen
Jun 1, 2016·Experimental Neurology·Baddreddine BoussadiaNicola Marchi
Aug 16, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Milu T CherianTaosheng Chen
Dec 31, 2015·European Journal of Medicinal Chemistry·Wenwei LinTaosheng Chen
May 15, 2018·Expert Opinion on Drug Metabolism & Toxicology·Cameron D BuchmanTaosheng Chen
Oct 1, 2017·Nature Communications·Wenwei LinTaosheng Chen
Dec 29, 2019·Molecular Pharmacology·Wenwei LinTaosheng Chen
Oct 21, 2020·Cells·Jenni KüblbeckPaavo Honkakoski
Dec 30, 2020·Biomedit︠s︡inskai︠a︡ khimii︠a︡·A V ShchulkinE N Yakusheva
Feb 3, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Sarah Da Won BaeJacob George
Oct 31, 2017·Pharmacology & Therapeutics·Elias J Fernandez
Nov 13, 2019·Journal of Chemical Information and Modeling·Bill PhamTongye Shen

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