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Updated: Feb 25, 2026

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

Daniel Flesch1, Sun-Yee Cheung1, Jurema Schmidt1

  • 1Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.

Journal of Medicinal Chemistry
|July 28, 2017
PubMed

Insights

Researchers developed a novel high-affinity farnesoid X receptor (FXR) modulator lacking acidic properties. This discovery offers a new therapeutic strategy for metabolic and liver diseases by potentially improving drug behavior.

Area of Science:

  • Biochemistry and Molecular Biology
  • Pharmacology and Drug Development
  • Hepatology and Metabolic Diseases

Background:

  • The farnesoid X receptor (FXR) is a critical cellular sensor for bile acids, regulating lipid, glucose, and bile acid homeostasis.
  • FXR plays a vital role in liver protection and has been validated as a therapeutic target for hepatic and metabolic diseases.
  • Existing potent FXR agonists possess a negatively ionizable function, which can negatively impact their pharmacokinetic properties.

Purpose of the Study:

  • To develop and characterize a novel high-affinity modulator of the farnesoid X receptor (FXR).
  • To investigate a FXR modulator that does not contain acidic residues, addressing limitations of current agonists.

Main Methods:

  • Chemical synthesis and characterization of a novel FXR modulator.
  • In vitro assays to determine binding affinity and functional activity at FXR.
  • Pharmacokinetic studies to evaluate distribution and behavior in vivo.

Main Results:

  • Successful development of a high-affinity FXR modulator.
  • The novel modulator lacks acidic functional groups.
  • Preliminary data suggests favorable pharmacokinetic properties compared to acidic FXR agonists.

Conclusions:

  • A novel, high-affinity FXR modulator without acidic residues has been developed.
  • This compound represents a promising new chemical entity for targeting FXR.
  • The absence of an acidic function may lead to improved pharmacokinetic profiles for treating liver and metabolic diseases.

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