MI-883 is orally active constitutive androstane receptor (CAR) ( EC 50 of 73 nM) agonist and pregnane X Receptor (PXR) ( IC50 of 100 nM) antagonist. MI-883 binds to CAR and PXR ligand-binding domains, promotes CAR LBD assembly, activates CAR3 variant, stimulates CAR cytoplasmic-nuclear translocation, upregulates CAR target genes, recruits coactivators NCOA1, NCOA2, NCOA3, inhibits basal and agonist-induced PXR activation, downregulates PXR target genes, disrupts PXR-NCOR2 interaction, blocks agonist-mediated PXR-NCOA1 recruitment. MI-883 reduces plasma total cholesterol, LDL cholesterol, and hepatic free cholesterol levels, increases fecal bile acid excretion, regulates genes involved in xenobiotic metabolism, cholesterol homeostasis, and bile acid homeostasis. MI-883 exhibits metabolic stability, liver-predominant distribution, a safety profile with no observed toxicity, and does not stimulate human hepatocyte hypertrophy or hyperplasia. MI-883 can be used for the research of diet-induced hypercholesterolemia [1].
In Vivo, MI-883 (5 mg/kg; p.o.; 3x per week; 4 weeks) significantly reduces plasma and hepatic free cholesterol levels and increases fecal bile acid excretion in humanized PXR-CAR-CYP3A4/CYP3A7 mice with diet-induced hypercholesterolemia, with no observed hepatotoxicity[1]. MI-883 (5 mg/kg; p.o.; every other day; 5 doses total) significantly reduces plasma total, LDL, and HDL cholesterol levels in humanized PXR-CAR-CYP3A4/CYP3A7 mice with high-cholesterol diet-induced hypercholesterolemia[1]. MI-883 (10 mg/kg; i.p.; once every 24 hours; 3 days) significantly induces hepatic Cyp2b10 mRNA expression but does not induce CYP3A4 mRNA expression in chow diet-fed humanized PXR-CAR-CYP3A4/3A7 mice[1]. MI-883 (2.5 mg/kg; p.o.; once daily; 7 days) does not significantly alter plasma cholesterol levels or hepatotoxicity biomarkers but induces hepatic CYP2B6 mRNA expression in PXB-mouse humanized liver mice[1].
In Vitro, MI-883 (10 pM-30 μM) potently activates recombinant human CAR LBD with an EC50 of 73 nM in a TR-FRET coactivator binding assay[1]. MI-883 (10 pM-30 μM; 24 h) activates human CAR LBD assembly in HepG2 cells with an EC50 of 0.38 μM[1]. MI-883 (10 pM-30 μM; 24 h) activates the human CAR3 variant in HepG2 cells with an EC50 of 0.38 μM[1]. MI-883 (10 pM-30 μM; 24 h) suppresses basal and Rifampicin -induced human PXR activation in HepG2 cells with IC50 values of 2.03 μM and 3.60 μM, respectively[1]. MI-883 (5 μM) stimulates translocation of the EGFP-CAR+A fusion protein to the nucleus in COS-1 cells, with ~90% nuclear localization observed[1]. MI-883 (1 μM, 5 μM, 10 μM; 24 h, 48 h) significantly upregulates CYP2B6 mRNA in HepaRG cells and primary human hepatocytes in a CAR-dependent manner, with no effect in CAR-ablated HepaRG KO CAR cells[1]. MI-883 (10 pM-30 μM) competes for binding to recombinant human PXR LBD with an IC50 of 0.10 μM in a TR-FRET competitive binding assay[1]. MI-883 (10 μM, 30 μM; 24 h) stimulates human PXR LBD assembly in HepG2 cells, confirming direct binding to the PXR ligand binding pocket[1]. MI-883 (10 μM, 30 μM; 24 h) acts as a PXR antagonist/inverse agonist in HepG2 cells, blocking rifampicin-induced coactivator recruitment and disrupting PXR-corepressor interactions[1]. MI-883 (1 μM, 5 μM, 10 μM, 20 μM; 24 h, 48 h) significantly downregulates basal and Rifampicin-induced CYP3A4 mRNA in LS174T cells, HepaRG cells, and primary human hepatocytes in a PXR-dependent manner, with no effect in PXR-ablated HepaRG KO PXR cells[1]. MI-883 (100 μM) recruits coactivators NCOA1, NCOA2, and NCOA3 to recombinant human CAR LBD, consistent with CAR agonist activity[1]. MI-883 (1 μM, 5 μM, 10 μM, 20 μM; 48 h) modulates expression of cholesterol and bile acid homeostasis genes in HepaRG cells and primary human hepatocytes, with CAR-dependent downregulation of SREBF1, PXR-dependent upregulation of LDLR, and complex regulation of CYP7A1 dependent on CAR presence[1]. MI-883 (5 μM; 8 h, 12 h, 24 h, 48 h, 72 h, 120 h) upregulates CYP2B6 mRNA and downregulates CYP3A4 mRNA in 3D primary human hepatocyte spheroids over a 120-hour treatment period[1]. MI-883 (5 μM; 72 h) does not reduce ATP production in 3D primary human hepatocyte spheroids after 72 hours of treatment, indicating no cytotoxicity[1]. MI-883 (5 μM; 72 h) does not upregulate proliferative biomarkers in 3D primary human hepatocyte spheroids after 72 hours of treatment, indicating no induction of hepatocyte proliferation[1].
References:
[1]. Dusek J, et al.. The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model. Nature communications. 2025 Feb 06;16(1):1418.
In Vivo, MI-883 (5 mg/kg; p.o.; 3x per week; 4 weeks) significantly reduces plasma and hepatic free cholesterol levels and increases fecal bile acid excretion in humanized PXR-CAR-CYP3A4/CYP3A7 mice with diet-induced hypercholesterolemia, with no observed hepatotoxicity[1]. MI-883 (5 mg/kg; p.o.; every other day; 5 doses total) significantly reduces plasma total, LDL, and HDL cholesterol levels in humanized PXR-CAR-CYP3A4/CYP3A7 mice with high-cholesterol diet-induced hypercholesterolemia[1]. MI-883 (10 mg/kg; i.p.; once every 24 hours; 3 days) significantly induces hepatic Cyp2b10 mRNA expression but does not induce CYP3A4 mRNA expression in chow diet-fed humanized PXR-CAR-CYP3A4/3A7 mice[1]. MI-883 (2.5 mg/kg; p.o.; once daily; 7 days) does not significantly alter plasma cholesterol levels or hepatotoxicity biomarkers but induces hepatic CYP2B6 mRNA expression in PXB-mouse humanized liver mice[1].
In Vitro, MI-883 (10 pM-30 μM) potently activates recombinant human CAR LBD with an EC50 of 73 nM in a TR-FRET coactivator binding assay[1]. MI-883 (10 pM-30 μM; 24 h) activates human CAR LBD assembly in HepG2 cells with an EC50 of 0.38 μM[1]. MI-883 (10 pM-30 μM; 24 h) activates the human CAR3 variant in HepG2 cells with an EC50 of 0.38 μM[1]. MI-883 (10 pM-30 μM; 24 h) suppresses basal and Rifampicin -induced human PXR activation in HepG2 cells with IC50 values of 2.03 μM and 3.60 μM, respectively[1]. MI-883 (5 μM) stimulates translocation of the EGFP-CAR+A fusion protein to the nucleus in COS-1 cells, with ~90% nuclear localization observed[1]. MI-883 (1 μM, 5 μM, 10 μM; 24 h, 48 h) significantly upregulates CYP2B6 mRNA in HepaRG cells and primary human hepatocytes in a CAR-dependent manner, with no effect in CAR-ablated HepaRG KO CAR cells[1]. MI-883 (10 pM-30 μM) competes for binding to recombinant human PXR LBD with an IC50 of 0.10 μM in a TR-FRET competitive binding assay[1]. MI-883 (10 μM, 30 μM; 24 h) stimulates human PXR LBD assembly in HepG2 cells, confirming direct binding to the PXR ligand binding pocket[1]. MI-883 (10 μM, 30 μM; 24 h) acts as a PXR antagonist/inverse agonist in HepG2 cells, blocking rifampicin-induced coactivator recruitment and disrupting PXR-corepressor interactions[1]. MI-883 (1 μM, 5 μM, 10 μM, 20 μM; 24 h, 48 h) significantly downregulates basal and Rifampicin-induced CYP3A4 mRNA in LS174T cells, HepaRG cells, and primary human hepatocytes in a PXR-dependent manner, with no effect in PXR-ablated HepaRG KO PXR cells[1]. MI-883 (100 μM) recruits coactivators NCOA1, NCOA2, and NCOA3 to recombinant human CAR LBD, consistent with CAR agonist activity[1]. MI-883 (1 μM, 5 μM, 10 μM, 20 μM; 48 h) modulates expression of cholesterol and bile acid homeostasis genes in HepaRG cells and primary human hepatocytes, with CAR-dependent downregulation of SREBF1, PXR-dependent upregulation of LDLR, and complex regulation of CYP7A1 dependent on CAR presence[1]. MI-883 (5 μM; 8 h, 12 h, 24 h, 48 h, 72 h, 120 h) upregulates CYP2B6 mRNA and downregulates CYP3A4 mRNA in 3D primary human hepatocyte spheroids over a 120-hour treatment period[1]. MI-883 (5 μM; 72 h) does not reduce ATP production in 3D primary human hepatocyte spheroids after 72 hours of treatment, indicating no cytotoxicity[1]. MI-883 (5 μM; 72 h) does not upregulate proliferative biomarkers in 3D primary human hepatocyte spheroids after 72 hours of treatment, indicating no induction of hepatocyte proliferation[1].
References:
[1]. Dusek J, et al.. The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model. Nature communications. 2025 Feb 06;16(1):1418.