Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics

The retinoid X receptors
(RXR) are ligand-activated transcription
factors involved in multiple regulatory networks as universal heterodimer
partners for nuclear receptors. Despite their high therapeutic potential
in many pathologies, targeting of RXR has only been exploited in cancer
treatment as the currently available RXR agonists suffer from exceptional
lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming
to overcome the limitations and to provide improved RXR ligands, we
developed a new potent RXR ligand chemotype based on the nonsteroidal
anti-inflammatory drug oxaprozin. Systematic structure–activity
relationship analysis enabled structural optimization toward low nanomolar
potency similar to the well-established rexinoids. Cocrystal structures
of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared
to current RXR agonists. The optimized compounds were highly selective
for RXR activation and induced RXR-regulated gene expression in native
cellular and in vivo settings suggesting them as
excellent chemical tools to further explore the therapeutic potential
of RXR.