ArticleBiology of reproduction2020
Metabolism of JQ1, an inhibitor of bromodomain and extra terminal bromodomain proteins, in human and mouse liver microsomes†.
Article in Biology of reproduction, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Article
- Targeting BRD4-A Promising Therapeutic Option for Glioblastoma?International journal of molecular sciences · 2026Review
- Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer.Cancers · 2024Article
- A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.Nucleic acids research · 2024Article
- Chemical Catalysis Guides Structural Identification for the MajorACS medicinal chemistry letters · 2024Article
- Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.Journal of medicinal chemistry · 2023Article
- Identifying the Reactive Metabolites of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using LC-MS-Based Metabolomic Approaches.Chemical research in toxicology · 2023Article
- Non-Hormonal Contraception.Journal of clinical medicine · 2023Review
- Article
- From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors.European journal of medicinal chemistry · 2023Article
- Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition.Scientific reports · 2023Article
- Epithelial to mesenchymal transition in mammary gland tissue fibrosis and insights into drug therapeutics.PeerJ · 2023Article
- Discovery of 3-Amino-1International journal of molecular sciences · 2022Article
- Viral Hijacking of BET Proteins.Viruses · 2022Review
- Noncanonical activation of GLI signaling in SOX2Science advances · 2022Article
- Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis.Acta pharmaceutica Sinica. B · 2022Article
- Article
- Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male contraceptive target. Although JQ1 possesses favourable physical properties, it exhibits a short half-life. Because the details of xenobiotic metabolism play important roles in the optimization of drug candidates and in determining the role of metabolism in drug efficacy, we investigated the metabolism of JQ1 in human and mouse liver microsomes. We present the first comprehensive view of JQ1 metabolism in liver microsomes, distinguishing nine JQ1 metabolites, including three monohydroxylated, one de-tert-butylated, two dihydroxylated, one monohydroxylated/dehydrogenated, one monohydroxylated-de-tert-butylated and one dihydroxylated/dehydrogenated variant of JQ1. The dominant metabolite (M1) in both human and mouse liver microsomes is monohydroxylated on the fused three-ring core. Using recombinant cytochrome P450 (CYP) enzymes, chemical inhibitors and the liver S9 fraction of Cyp3a-null mice, we identify enzymes that contribute to the formation of these metabolites. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is the main contributor to the production of JQ1 metabolites in vitro, and the CYP3A4/5 inhibitor ketoconazole strongly inhibits JQ1 metabolism in both human and mouse liver microsomes. Our findings suggest that JQ1 half-life and efficacy might be improved in vivo by co-administration of a selective CYP inhibitor, thereby impacting the use of JQ1 as a probe for BRDT activity in spermatogenesis and as a probe or therapeutic in other systems.
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