Structure-guided design of a highly potent RXR agonist with superior physicochemical properties

Retinoid X receptors (RXR, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration and metabolic diseases but traditional RXR agonists mimicking the natural ligand 9-cis retinoic acid exhibit poor physicochemical properties, pharmacokinetics and safety profiles. Improved RXR ligands are needed to exploit RXR modulation as a promising therapeutic concept in various indications beyond its current role in second-line cancer treatment. Here we report the co-crystal structure of RXR in complex with a novel pyrimidine-based ligand and the structure-informed optimization of this scaffold to highly potent and highly soluble RXR agonists. Rigidization resulted in significantly improved potency and focused structure-activity relationship elucidation indicated potential avenues to RXRα preference. We obtained an optimized RXR agonist with low nanomolar potency, no cytotoxic activity and very favorable physicochemical properties highlighting this promising scaffold for the development of next-generation RXR agonist drugs.