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.