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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Modulation of RXR function through ligand design

Efrén Pérez1, William Bourguet, Hinrich Gronemeyer

  • 1Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, Spain.

Biochimica Et Biophysica Acta
|April 26, 2011
PubMed

Insights

Retinoid X receptors (RXRs) are crucial nuclear receptors targeted for drug discovery. While RXR modulators show promise for cancer and metabolic diseases, side effects complicate their development, necessitating selective rexinoids.

Area of Science:

  • Nuclear Receptor Superfamily
  • Endocrinology
  • Molecular Biology

Background:

  • Retinoid X receptors (RXRs) are promiscuous partners in nuclear receptor heterodimers, crucial for transcriptional regulation.
  • Heterodimers can be permissive (activated by rexinoids or partner ligands) or non-permissive (requiring both).
  • RXR modulators are explored for cancer and metabolic diseases, with a rexinoid already in clinical use.

Purpose of the Study:

  • To review the modulation of PPARγ/RXR and LXR/RXR heterodimer activities by rexinoids.
  • To discuss the therapeutic potential and limitations of RXR modulators in metabolic diseases.
  • To highlight the need for selective rexinoids to overcome adverse effects.

Main Methods:

  • Review of genetic and pharmacological data from animal models of metabolic diseases.
  • Analysis of RXR heterodimer function and ligand-receptor interactions.
  • Focus on PPARγ/RXR and LXR/RXR heterodimer modulation by rexinoids.

Main Results:

  • RXR agonists and antagonists show potential as anti-obesity agents.
  • RXR modulation can lead to adverse effects like elevated triglycerides, suppressed thyroid axis, and hepatomegaly.
  • Selective PPARγ/RXR and LXR/RXR rexinoids may offer improved therapeutic profiles.

Conclusions:

  • RXR modulators hold therapeutic promise but face development challenges due to side effects.
  • Development of heterodimer-selective rexinoids is crucial for overcoming limitations.
  • Targeting specific RXR heterodimers could lead to safer and more effective treatments for metabolic diseases.

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