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Tuning RXR Modulators for PGC1α Recruitment.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Sep 26; Vol. 67 (18), pp. 16338-16354. Date of Electronic Publication: 2024 Sep 11. - Publication Year :
- 2024
-
Abstract
- The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. The ability of RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue to tissue- or gene-selective RXR activation. Here, we identified strong induction of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) binding to RXR by a synthetic agonist but not by the endogenous ligand 9-cis retinoic acid. Structure-guided diversification of this lead resulted in a set of three structurally related RXR agonists with different ability to promote PGC1α recruitment in cell-free and cellular context. These results demonstrate that selective modulation of coregulator recruitment to RXR can be achieved with molecular glues and potentially open new therapeutic opportunities by targeting the ligand-induced RXR-PGC1α interaction.
- Subjects :
- Humans
Ligands
Tretinoin pharmacology
Tretinoin chemistry
Tretinoin metabolism
Structure-Activity Relationship
Alitretinoin pharmacology
Alitretinoin chemistry
Alitretinoin metabolism
Protein Binding
HEK293 Cells
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
Retinoid X Receptors agonists
Retinoid X Receptors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39258574
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c01231