Tuning RXR Modulators for PGC1α Recruitment

Area of Science:

• Molecular biology
• Endocrinology
• Pharmacology

Background:

• Nuclear retinoid X receptors (RXRs) regulate gene expression via ligand-dependent corepressor release and coactivator recruitment.
• The diverse coactivator binding of RXRs suggests potential for selective activation through ligand modulation.
• Targeting RXR-coregulator interactions could enable tissue- or gene-selective therapeutic strategies.

Purpose of the Study:

• To investigate the selective recruitment of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) to RXR by synthetic agonists.
• To develop novel RXR agonists capable of differential PGC1α interaction for therapeutic applications.

Main Methods:

• Identification of a synthetic agonist that strongly induces PGC1α binding to RXR.
• Structure-guided design and synthesis of related RXR agonists.
• Assessment of PGC1α recruitment in cell-free and cellular assays.

Main Results:

• A synthetic agonist, distinct from 9-cis retinoic acid, significantly enhanced PGC1α binding to RXR.
• Structurally related agonists exhibited varying capacities for promoting PGC1α recruitment.
• Selective modulation of RXR-PGC1α interaction was demonstrated in both in vitro and cellular settings.

Conclusions:

• Ligand-induced selective coregulator recruitment to RXR is achievable using molecular glues.
• Targeting the RXR-PGC1α interaction presents a promising avenue for developing novel therapeutics.
• This approach may lead to new treatment strategies by exploiting RXR pathway selectivity.