Structural Tuning of Partial RXR Agonism and Antagonism

Retinoid X receptors (RXRs) represent a central switch
in nuclear
receptor signaling and appear to hold therapeutic potential in diverse
indications. However, the ability of RXR agonists to activate multiple
nuclear receptor heterodimers gives rise to adverse effects, which
may be avoided by partial RXR agonism. In exploring the SAR of a partial
agonist scaffold, we identified a region that allowed tuning of RXR
activation efficacy between various levels of partial agonism and
antagonism. Co-crystal structure analysis revealed dual steric pressure
and a combination of reciprocal structural effects to mediate partial
agonist activity providing a molecular basis for structural tuning
of RXR modulators.