Development of an RXR Agonist Scaffold with Pronounced Homodimer Preference

The activation of retinoid X receptors (RXRs) presents promising therapeutic potential in diverse conditions, such as cancer, inflammation, metabolic dysfunction, and neurodegeneration. However, RXRs play a central role in nuclear receptor signaling and act in various dimeric forms with multiple other ligand-activated transcription factors giving rise to promiscuous effects of RXR agonists. Here we identified a new RXR ligand chemotype addressing only part of RXR's molecular activities. Optimization provided a new RXR modulator scaffold fully activating the RXR homodimer with nanomolar potency but displaying markedly reduced RXR heterodimer activation compared to bexarotene. Co-crystal structure analysis revealed different molecular effects on the RXR LBD conformation than bexarotene possibly mediating the selective activity. The new RXR modulator type enables studies on selective RXR homodimer activation effects and suggests that different molecular mechanisms of RXR activity can be selectively addressed with ligands.