Related Experiment Video

Updated: Sep 11, 2025

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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Structural Basis of PPARγ-Mediated Transcriptional Repression by the Covalent Inverse Agonist FX-909

Zane T Laughlin1, Liudmyla Arifova1,2, Paola Munoz-Tello1

  • 1Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.

Journal of Medicinal Chemistry
|August 13, 2025
PubMed

Insights

FX-909, a novel drug, effectively inhibits bladder cancer by targeting peroxisome proliferator-activated receptor gamma (PPARγ). This covalent inverse agonist demonstrates superior repression of PPARγ activity compared to older compounds.

Area of Science:

  • Molecular biology
  • Oncology
  • Pharmacology

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARγ) hyperactivation fuels urothelial (bladder) cancer growth.
  • Compounds inhibiting PPARγ activity offer a therapeutic strategy for bladder cancer.

Purpose of the Study:

  • To compare the mechanism of action of FX-909, a covalent PPARγ inverse agonist, with other related compounds.
  • To elucidate the structural basis for FX-909's improved PPARγ inverse agonism.

Main Methods:

  • Functional profiling and Nuclear Magnetic Resonance (NMR) studies were employed.
  • Crystal structure determination of PPARγ ligand-binding domain (LBD) complexed with FX-909 and a corepressor peptide.

Main Results:

  • FX-909 exhibits enhanced corepressor-selective inverse agonism compared to T0070907.
  • FX-909 stabilizes a transcriptionally repressive PPARγ LBD conformation more effectively.
  • The crystal structure reveals a shared repressive conformation among covalent inverse agonists.

Conclusions:

  • FX-909 represents a pharmacologically significant and clinically relevant PPARγ inverse agonist.
  • These findings underscore the therapeutic potential of transcriptionally repressive PPARγ inverse agonists in bladder cancer.

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