Rational Design of a New RXR Agonist Scaffold Enabling Single-Subtype Preference for RXRα, RXRβ, and RXRγ

The three retinoid X receptor subtypes (RXRα, RXRβ,
RXRγ) exhibit critical regulatory roles in cell proliferation
and differentiation, metabolism, and inflammation. Due to their importance
in nuclear receptor signaling, RXRs are widely distributed and pan-RXR
agonists cause adverse effects, but the three highly conserved RXR
ligand binding sites render the development of subtype-selective ligands
a major challenge. We have fused elements of known RXR ligands to
obtain a new RXR agonist chemotype on which minor structural modifications
enabled the development of tools with single-subtype preference for
RXRα, RXRβ, and RXRγ. Molecular modeling indicated
different binding conformations and interaction patterns with the
RXR LBDs as factors of preferential binding. In a phenotypic adipocyte
differentiation experiment, only the RXRα preferential tool
enhanced the adipogenic effects of pioglitazone, suggesting this subtype
as particularly relevant in adipogenesis and highlighting the set
of subtype-preferential RXR agonist tools as suitable for functional
cellular studies.