Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation

Abstract

The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferatoractivated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure−activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.

Molecular tuning of farnesoid X receptor partial agonism

“…The amounts of the test compound were quantified by external calibration. The metabolism experiments showed the following results (expressed as mean ± SEM% remaining compound; n = 4): 0 min: 96 ± 1%; 15 min: 84 ± 3%; 30 min: 77 ± 2%; 60 min: 63 ± 2% 40 .…”

Association between <i>in vitro</i> nuclear receptor-activating profiles of chemical compounds and their <i>in vivo</i> hepatotoxicity in rats

“…Among the RXRα-positives, S175, S254 and S325 exhibited stronger agonist activities than the others. Among them, S325 was recently reported as an agonist of human RXRα (Pollinger et al, 2019). Notably, the RXRα activation levels of S175 and S254 at 100 μM were almost comparable to BEX (10 nM).…”

Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARγ Modulator

“…The Gal4-fusion receptor plasmids pFA-CMV-hPPARα-LBD (uniprot Q07869, residues 164–466), pFA-CMV-hPPARδ-LBD (uniprot Q03181, residues 138–441), pFA-CMV-hPPARγ-LBD (uniprot P37231, residues 203–505), pFA-CMV-hLXRα-LBD (uniprot Q13133, residues 182–447), pFA-CMV-hRARα-LBD (uniprot P10276-1, residues 177–462), pFA-CMV-hVDR-LBD (uniprot P11473-1, residues 119–427), pFA-CMV-hCAR-LBD (uniprot entry Q4994-6, residues 48–324), and pFA-CMV-hPXR-LBD (uniprot O75469-1, residues 138–434) coding for the hinge region and ligand binding domain (LBD) of the canonical isoform of the respective nuclear receptor have been cloned by integrating cDNA fragments obtained from PCR amplification of commercial cDNA (Source BioScience, Nottingham, UK) or obtained from PCR amplification of human monocytes into the BamH1 cleavage site of the pFA-CMV vector (Stratagene, La Jolla, CA, USA) and, in some cases, an afore inserted Kpn I cleavage site as reported previously. − pFR-Luc (Stratagene) was used as reporter plasmid and pRL-SV40 (Promega) for normalization of transfection efficiency and cell growth.…”