CINPA1 is a ligand-binding domain (LBD)-targeting constitutive androstane receptor (CAR) inhibitor that prevents CAR recruitment to promoter regions of regulated genes (by >85%; 1 μM CINPA1 against 0.1 μM CITCO-induced CAR recruitment to CYP2B6 or CYP3A4 promoters; human hepatocytes) by altering CAR-coregulator interactions. CINPA1 inhibits CAR-mediated transcription in a potent (IC50 = 70 nM; HepG2-hCAR1 CYP2B6-luc reporter cells) and selective manner with only weak PXR antagonist potency (68% inhibition by 18 μM CINPA1 against 5 μM rifampicin; HepG2-PXR reporter cells) and no cytotoxicity or agonist/antagonist activity toward FXR, GR, LXRα/β, PPARγ, RXRα/β, VDR.
European journal of medicinal chemistry, 108, 505-528 (2015-12-31)
Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that regulate the expression of drug-metabolizing enzymes and efflux transporters. CAR activation promotes drug elimination, thereby reducing therapeutic effectiveness, or causes adverse drug effects via toxic metabolites.
Nuclear receptors (NRs) are a group of transcription factors emerging as players in normal and pathological CNS development. Clinically, an association between the constitutive androstane NR (CAR) and cognitive impairment was proposed, however never experimentally investigated. We wished to test
Drug metabolism and disposition: the biological fate of chemicals, 44(11), 1759-1770 (2016-08-16)
The constitutive androstane receptor (CAR) regulates the expression of genes involved in drug metabolism and other processes. A specific inhibitor of CAR is critical for modulating constitutive CAR activity. We recently described a specific small-molecule inhibitor of CAR, CINPA1 (ethyl
The constitutive androstane receptor (CAR) plays an important role in xenobiotic metabolism, energy homeostasis, and cell proliferation. Antagonism of the CAR represents a key strategy for studying its function and may have potential clinical applications. However, specific human CAR (hCAR)
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