Related Experiment Video

Updated: Sep 15, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
10:51

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, United States 37232.

Biorxiv : the Preprint Server for Biology
|July 14, 2025
PubMed

Insights

FX-909, a novel drug, effectively inhibits bladder cancer growth by repressing peroxisome proliferator-activated receptor gamma (PPARγ) activity. This compound shows improved selectivity and stabilization of a transcriptionally repressive PPARγ conformation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Pharmacology

Background:

  • Hyperactivation of peroxisome proliferator-activated receptor gamma (PPARγ) drives urothelial cancer growth.
  • Pharmacological inhibition of PPARγ is a therapeutic strategy for bladder cancer.
  • FX-909 is an investigational covalent PPARγ inverse agonist for advanced solid tumors, including bladder cancer.

Purpose of the Study:

  • To compare the mechanism of action of FX-909 with other covalent PPARγ inverse agonists.
  • To elucidate the structural basis for FX-909's selective inverse agonism.
  • To highlight the clinical relevance of transcriptionally repressive PPARγ inverse agonists.

Main Methods:

  • Functional profiling assays.
  • Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Crystallography of the 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 more effectively stabilizes a transcriptionally repressive PPARγ LBD conformation.
  • Structural analysis revealed a shared repressive conformation among covalent inverse agonists.

Conclusions:

  • FX-909 demonstrates improved pharmacological properties as a PPARγ inverse agonist.
  • The findings support the development of transcriptionally repressive PPARγ inverse agonists for cancer therapy.
  • FX-909's mechanism is crucial for its potential in treating muscle-invasive bladder cancer.

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