ArticleMolecular pharmacology2015
CINPA1 is an inhibitor of constitutive androstane receptor that does not activate pregnane X receptor.
Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- Genome-wide analysis reveals ligand-dependent allostery in RARα:RXR-mediated transcriptional regulation.Cell reports · 2026Article
- Mechanistic insights into CAR-mediated repression of the HNF4α-FABP1 axis and inhibition of HepG2 cell proliferation.Pharmacological research · 2026Article
- Constitutive Androstane Receptor Regulates Germ Cell Homeostasis, Sperm Quality, and Male Fertility via Akt-Foxo1 Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Regulation of the Organic Anion Transporting Polypeptide 1B3 (OATP1B3) by Sex Hormones.Bulletin of experimental biology and medicine · 2024Article
- The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma.Cell death discovery · 2024Article
- Proanthocyanidin B2 derived metabolites may be ligands for bile acid receptors S1PR2, PXR and CAR: anJournal of biomolecular structure & dynamics · 2024Article
- The Role of Adopted Orphan Nuclear Receptors in the Regulation of an Organic Anion Transporting Polypeptide 1B1 (OATP1B1) under the Action of Sex Hormones.Current issues in molecular biology · 2023Article
- Hidden modes of DNA binding by human nuclear receptors.Nature communications · 2023Article
- Discovery of Novel Human Constitutive Androstane Receptor Agonists with the Imidazo[1,2-Journal of medicinal chemistry · 2023Article
- Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Assessment of Malondialdehyde Belonging to Modulators and Substrates of the P-Glycoprotein Transporter Protein.Doklady. Biochemistry and biophysics · 2022Article
- Article
- Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation.Nucleic acids research · 2022Article
- Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes.Cells · 2021Article
- Review
- CITCO Directly Binds to and Activates Human Pregnane X Receptor.Molecular pharmacology · 2020Article
- High-content analysis of constitutive androstane receptor (CAR) translocation identifies mosapride citrate as a CAR agonist that represses gluconeogenesis.Biochemical pharmacology · 2019Article
- Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor.Drug discovery today · 2019Review
- CINPA1 binds directly to constitutive androstane receptor and inhibits its activity.Biochemical pharmacology · 2018Article
- A current structural perspective on PXR and CAR in drug metabolism.Expert opinion on drug metabolism & toxicology · 2018Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.