Comparative evaluation of the biological characteristics of a novel retinoid X receptor agonist and bexarotene.

Abstract

The retinoid X receptor (RXR) belongs to the nuclear receptor superfamily, which regulates various physiological processes. RXR agonists, classified as rexinoids, exhibit selectivity for RXR over the retinoic acid receptor and have therapeutic potential against cancer, metabolic disorders, and Alzheimer disease (AD). Here, we characterized the biological properties of 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B, and found that it exhibited potent RXRα agonist activity comparable with that of the clinically used RXR agonist bexarotene, but lower agonist activity toward retinoic acid receptor α and RXRγ. RNA-sequencing-based transcriptome analysis of microglial cells revealed that 6OHA and Bex induced similar gene expression patterns; however, 6OHA was more associated strongly with chemotaxis and response to stimuli. Pharmacokinetic studies showed a higher C_max, faster T_max, and more rapid clearance in both the serum and brain for 6OHA than for Bex. Although 6OHA exhibited a higher area under the concentration-time curve from 0 to 6 hours in serum, its area under the concentration-time curve from 0 to 6 hours in the brain was lower than that of Bex. Together with gene expression data, these findings suggest that 6OHA is a more effective RXR agonist in peripheral tissues while maintaining comparable efficacy in the brain. Furthermore, unlike Bex, 6OHA did not increase serum triglycerides or decrease serum thyrotropin and free thyroxine levels, likely reflecting its distinct pharmacologic profile from that of Bex. Collectively, these results suggest that 6OHA is a promising RXR agonist with minimal adverse effects and potential application in treating cancer, AD, and metabolic disorders. SIGNIFICANCE STATEMENT: Despite the potential of retinoid X receptor (RXR) agonists, their application has been limited by adverse effects. The novel RXR agonist 6OHA exhibits potent RXRα agonist activity while showing lower activities for retinoid acid receptor α and RXRγ than the RXR agonist bexarotene. Moreover, 6OHA also shows favorable pharmacokinetics and a gene expression profile distinct from Bex. These properties may account for the minimal adverse effects of 6OHA and support its potential as a therapeutic RXR agonist.