title: An insulin-like growth factor 1 receptor inhibitor induces CYP3A4 expression through a pregnane X receptor-independent, noncanonical constitutive androstane receptor-related mechanism.
abstract: Inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling represents an attractive therapeutic strategy for cancer treatment. A first-generation IGF-1R inhibitor (R)-4-(3-(3-chlorophenyl)-3-hydroxypropyl)-3-(4-methyl-6-morpholino-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-536924), however, was associated with potent CYP3A4 induction mediated by pregnane X receptor (PXR; NR1I2) transactivation. Structural activity-based modification led to the synthesis of 4-(1-(2-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-1H-benzo[d]imidazol-6-yl)piperidin-4-yl) piperazine-1-carboxylate (BMS-665351) with no PXR activity while maintaining its ability to inhibit IGF-1R. However, BMS-665351 significantly induces CYP3A4 expression in human primary hepatocytes (HPHs). Here, we report a novel nonclassical constitutive androstane receptor (CAR; NR1I3)-related pathway of BMS-665351-mediated CYP3A4 induction. BMS-665351 treatment resulted in the significant induction of CYP3A4 in HPHs and HepG2 cells, but failed to activate either PXR or CAR in cell-based reporter assays. Moreover, BMS-665351 at concentrations that induce CYP3A4 expression was unable to translocate human CAR from the cytoplasm to the nucleus of HPHs, which represents the initial step of CAR activation. Nevertheless, quantitative polymerase chain reaction analysis demonstrated that BMS-665351 significantly enhanced the expression of CYP3A4 in CAR- but not PXR-transfected HepG2 and Huh7 cells. It is noteworthy that BMS-665351 selectively induced the expression of CAR but not PXR in all tested hepatic cell systems. Synergistic induction of CYP3A4 was observed in HPHs cotreated with BMS-665351 and prototypical activators of CAR but not PXR. In summary, our results indicate that BMS-665351-mediated induction of CYP3A4 is CAR-dependent, but BMS-665351 itself is not a typical activator of either CAR or PXR, rather it functions as a selective inducer of CAR expression and increases CYP3A4 through a noncanonical CAR-related mechanism.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Linhao
authors.initials: L
authors.lastname: Li
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sinz
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D001562:Benzimidazoles / Q000494:pharmacology*; D000090702:Constitutive Androstane Receptor; D003513:Cycloheximide / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*
chemical_list: C571286:4-(1-(2-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-1H-benzo(d)imidazol-6-yl)piperidin-4-yl)piperazine-1-carboxylate; D001562:Benzimidazoles; D000090702:Constitutive Androstane Receptor; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; D010879:Piperazines; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D003609:Dactinomycin; D003513:Cycloheximide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017526:Receptor, IGF Type 1