Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties

Retinoid X receptors (RXRs, 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. Focused structure–activity
relationship elucidation and rigidization resulted in a substantially
optimized partial 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
targeting drugs.