Structure-Guided Development of MAD22 as a Next-Generation RXR Agonist

Retinoid X receptors (RXRα, RXRβ, RXRγ) are ligand-activated transcription factors acting as universal nuclear receptor heterodimer partners, and regulating cell proliferation, differentiation, metabolism and inflammation. RXRs hold therapeutic potential in multiple indications like metabolic and inflammatory diseases, cancer and neurodegeneration. However, adverse effects of synthetic RXR agonists (so-called rexinoids), which are due to a lack of RXR (subtype) selectivity, as well as poor physicochemical and pharmacokinetic properties, hinder their application beyond second-line cancer treatment.

To address limitations of traditional rexinoids, we developed a novel pyrimidine-based RXR agonist lead, JP147 (1), with improved properties and slight RXRα preference. Guided by the co-crystal structure of 1 bound to RXRα (PDB ID: 8pp0), we conducted systematic structure-activity relationship (SAR) studies and identified the highly potent RXR partial agonist ML197 (2) bearing a 4,4-dimethyl-1,2,3,4-tetrahydroquinoline motif in the 6' pyrimidine position. Further modifications revealed β-alanine as optimal substituent for the 2' position and trifluoromethyl for the 4' position. Structural fusion based on all SAR knowledge yielded the RXR agonist MAD22 (3) exhibiting single-digit nanomolar potency (EC₅₀ (RXRα) 3.0 nM), no cytotoxicity, and >100-fold selectivity over nuclear receptors related to or forming dimers with RXR. High-affinity binding to RXR (Kd 0.008 µM) was confirmed by isothermal titration calorimetry (ITC), and reporter gene assays using the response elements DR1 and RARE demonstrated strong preference for the RXR homodimer (0.002 µM). Additionally, 3 revealed remarkable physicochemical and pharmacokinetic characteristics including superior aqueous solubility (114 µM, >260-fold higher than bexarotene) and high microsomal stability (t_1/2 >2h). These results highlight 3 as a next-generation RXR agonist with exceptional drug-like properties.