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Updated: Apr 29, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

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Bazedoxifene-scaffold-based mimetics of solomonsterols A and B as novel pregnane X receptor antagonists

Žiga Hodnik1, Lucija Peterlin Mašič, Tihomir Tomašić

  • 1Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.

Journal of Medicinal Chemistry
|May 16, 2014
PubMed

Insights

Researchers discovered novel bazedoxifene-based compounds that act as Pregnane X receptor (PXR) antagonists. These PXR antagonists show potential in overcoming drug resistance in cancer by inhibiting PXR-regulated drug metabolism.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Pregnane X receptor (PXR) is a nuclear receptor that regulates drug metabolism and is overexpressed in cancers, contributing to multidrug resistance.
  • PXR is a key target for developing anticancer therapies to overcome drug resistance.

Purpose of the Study:

  • To discover novel PXR antagonists based on a bazedoxifene scaffold.
  • To evaluate the potential of these compounds in suppressing PXR-mediated drug metabolism and overcoming drug resistance.

Main Methods:

  • Synthesis of bazedoxifene-scaffold-based compounds.
  • Luciferase reporter assay using PXR-transfected HepG2 cells to identify PXR antagonists.
  • Structure-activity relationship studies to optimize antagonist activity.
  • Evaluation of PXR antagonists' effect on PXR expression and CYP3A4 induction.

Main Results:

  • Compounds 19-24 were identified as promising PXR antagonists.
  • Compound 20 exhibited potent PXR antagonistic activity (IC50 = 11 μM).
  • Hydroxyl groups were found to be crucial for PXR antagonistic activity.
  • Compounds 20 and 24 downregulated PXR expression and inhibited PXR-induced CYP3A4 expression.

Conclusions:

  • Novel bazedoxifene-scaffold-based PXR antagonists were successfully discovered.
  • These antagonists demonstrate potential for suppressing PXR-regulated drug metabolism and could be valuable in anticancer drug resistance strategies.

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