Natural and Structure-based RXR Ligand Scaffolds and Their Functions

Area of Science:

• Molecular Endocrinology
• Structural Biology
• Drug Discovery

Background:

• Retinoid X receptors (RXRs) are nuclear receptors that form heterodimers with various partners, modulating gene expression.
• RXRs play crucial roles in cellular processes, including nutrient metabolism, and are implicated in diseases like cancer and metabolic disorders.
• Ligands for RXRs, known as rexinoids, can act as agonists, partial agonists, inverse agonists, or antagonists, influencing RXR function.

Purpose of the Study:

• To explore the therapeutic potential of RXR modulators (rexinoids) in treating diseases such as cancer and metabolic disorders.
• To understand how the structural diversity of rexinoids influences their interaction with RXR and co-regulators.
• To investigate the challenges in predicting the correlation between rexinoid structure and physiological response, especially for heterodimer-selective compounds.

Main Methods:

• Review of existing literature on RXR structure-function relationships and rexinoid design.
• Analysis of ligand-receptor complex structures determined by X-ray crystallography and molecular modeling.
• Examination of the cell and context-dependent interactions of RXR-ligand complexes with co-regulators.

Main Results:

• Rexinoids modulate RXR activity, impacting gene networks involved in metabolism and disease.
• A rexinoid, bexarotene, is clinically approved for cutaneous T-cell lymphoma, demonstrating therapeutic viability.
• Rational drug design, based on structural information, has yielded diverse rexinoids, but predicting physiological outcomes remains complex.

Conclusions:

• RXR modulators offer significant therapeutic potential for a range of diseases.
• Understanding the structural basis of RXR modulation is advancing, but predicting specific physiological responses requires further research.
• Further investigation into rexinoid structure-activity relationships is crucial for optimizing therapeutic applications, particularly for selective rexinoids.