Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles

Author(s)

Burk, Oliver ^{[1, 2]} ; Kuzikov, Maria ^[3] ; Kronenberger, Thales ^{[4, 3]} ; Jeske, Judith ^{[1, 2]} ; Keminer, Oliver ^[3] ; Thasler, Wolfgang E. ^[5] ; Schwab, Matthias ^{[1, 2, 6, 7]} ; Wrenger, Carsten ^[4] ; Windshuegel, Bjoern ^[3]

Affiliation

^[1] Univ Tubingen, Tubingen - Germany

^[2] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart - Germany

^[3] Fraunhofer Inst Mol Biol & Appl Ecol IME, Schnackenburgallee 114, D-22525 Hamburg - Germany

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo - Brazil

^[5] Univ Munich, Dept Gen Visceral Transplantat & Vasc Surg, Campus Grosshadern, Munich - Germany

^[6] Univ Hosp Tubingen, Dept Clin Pharmacol, Tubingen - Germany

^[7] Univ Tubingen, Dept Pharm & Biochem, Tubingen - Germany

• Document type: Journal article
• Source: ARCHIVES OF TOXICOLOGY; v. 92, n. 4, p. 1435-1451, APR 2018.
• Web of Science Citations: 2

Abstract

Activation of pregnane X receptor (PXR) results in the induction of first-pass metabolism and drug efflux. Hereby, PXR may cause adverse drug reactions or therapeutic failure of drugs. PXR inhibition is thus an attractive option to minimise adverse effects or to improve therapeutic efficiencies; however, only a limited number of antagonists have been identified so far. We performed a cell-based high-throughput screen to identify PXR antagonists, using a library of approved and investigational drugs. Two approved drugs, pimecrolimus and pazopanib, emerged as novel potent antagonists of PXR activation, with IC50 values of 1.2 and 4.1 mu M, respectively. We further characterised these with respect to receptor specificity, assembly of the PXR ligand-binding domain (LBD) and interactions with co-factors. In vitro and in silico assays were carried out to identify the site(s) of interaction with the PXR LBD. Primary human hepatocytes were used to investigate antagonism of the induction of endogenous PXR target genes. Pimecrolimus and pazopanib did not affect the transcriptional activity of other nuclear receptors. Both induced the release of co-repressor from PXR and likewise interfered with agonist-induced recruitment of co-activator. Cumulative evidence from cellular and in vitro assays, as well as molecular docking, suggested additional or exclusive binding outside the PXR ligand-binding pocket for both. The compounds differentially antagonised the induction of PXR-regulated genes by rifampicin in primary human hepatocytes. In conclusion, we here have identified two approved drugs as novel potent PXR inhibitors with differential receptor interaction profiles and gene selectivity in primary human hepatocytes. (AU)

• FAPESP's process: 14/27313-1 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening
• Grantee: Thales Kronenberger
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/03644-9 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening
• Grantee: Thales Kronenberger
• Support Opportunities: Scholarships in Brazil - Doctorate