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Tuning RXR Modulators for PGC1α Recruitment.

Authors :
Nawa F
Sai M
Vietor J
Schwarzenbach R
Bitić A
Wolff S
Ildefeld N
Pabel J
Wein T
Marschner JA
Heering J
Merk D
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.

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