Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist Potency

The retinoid X receptors (RXRs) are
ligand-activated transcription
factors involved in, for example, differentiation and apoptosis regulation.
Currently used reference RXR agonists suffer from insufficient specificity
and poor physicochemical properties, and improved tools are needed
to capture the unexplored therapeutic potential of RXR. Endogenous
vitamin A-derived RXR ligands and the natural product RXR agonist
valerenic acid comprise acrylic acid residues with varying substitution
patterns to engage the critical ionic contact with the binding site
arginine. To mimic and exploit this natural ligand motif, we probed
its structural fusion with synthetic RXR modulator scaffolds, which
had profound effects on agonist activity and remarkably boosted potency
of an oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement
of the acrylic acid to overcome its pan-assay interference compounds
(PAINS) character enabled the development of a highly optimized RXR
agonist chemical probe.