Ligand Screening System for the RXRα Heterodimer Using the Fluorescence RXR Agonist CU-6PMN

Abstract

Retinoid X receptor (RXR), a nuclear receptor (NR) that regulates transcription of target genes in a ligand binding-dependent manner, is of interest as a drug target. RXR agonists have been developed as therapeutic agents for cutaneous invasive T-cell lymphoma (e.g., bexarotene (1)) and investigated as potential anti-inflammatory agents. Screening systems for the binding of RXR alone have been reported. However, although RXRs function as RXR heterodimers, information on systems to evaluate the differential binding of RXR agonists as RXR heterodimers has not been available until recently. Here we show that the fluorescent RXR agonist CU-6PMN (3), designed by our group, can be useful for assessing RXR binding to PPARγ/RXRα, and that the binding data differ from those of RXRα alone. This screening method opens a new avenue for binding assays for RXR heterodimers.

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

“…In addition to yielding the exceptionally potent pan-RXR agonist 33, the structure-informed optimization of 2 indicated possibly an avenue to RXR agonists with relevant RXRα selectivity. The lead 2 already exhibited slightly RXRα preferential agonism and several structural features (3,9,26,29,32) retained or enhanced this preference to up to a factor of 14 (32). Hence, we evaluated whether the fusion of these modifications was additive in terms of conveying RXRα selectivity (Table 7).…”

“…Retinoid X receptors (RXRα, RXRβ, RXRγ; NR2B1–3) are ligand-activated transcription factors exhibiting a prominent role in nuclear receptor signaling as universal heterodimer partners. − For their widespread distribution over all tissues and cell types, and their importance in the nuclear receptor network, RXRs have a regulatory role in multiple physiological processes and hold therapeutic potential in various pathologies such as metabolic and inflammatory diseases, cancer, and neurodegeneration. ,− Fatty acid and vitamin A metabolites − act as natural RXR ligands with varying potency and activate the receptors’ transcriptional activity in permissive heterodimers or homodimers. Various synthetic Rexionoids have been developed mainly for indications in oncology among which only bexarotene ( 1 , Table ) holds drug approval and is used for second-line cancer treatment.…”

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

“…Retinoid X receptors (RXRα, RXRβ, RXRγ; NR2B1-3) are ligand-activated transcription factors exhibiting a prominent role in nuclear receptor signaling as universal heterodimer partners [1][2][3] . For their widespread distribution over all tissues and cell types, and their importance in the nuclear receptor network, RXRs have a regulatory role in multiple physiological processes and hold therapeutic potential in various pathologies like metabolic and inflammatory diseases, cancer and neurodegeneration 2,[4][5][6][7][8] .…”