AI Article Synopsis
- Retinoid X receptors (RXRs) are important proteins that help regulate various biological processes like cell differentiation and death, but existing RXR agonists lack specificity and effectiveness.
- Researchers are working to develop better RXR modulators by combining structures from natural ligands, like those derived from vitamin A and valerenic acid, to enhance their binding properties and effectiveness.
- They successfully created a new, more potent RXR agonist by modifying an oxaprozin-derived compound and replacing problematic elements to avoid interference in biological assays, leading to a highly optimized new chemical probe for RXR.
Article Abstract
The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference RXR agonists suffer from insufficient specificity and poor physicochemical properties, and improved tools are needed to capture the unexplored therapeutic potential of RXR. Endogenous vitamin A-derived RXR ligands and the natural product RXR agonist valerenic acid comprise acrylic acid residues with varying substitution patterns to engage the critical ionic contact with the binding site arginine. To mimic and exploit this natural ligand motif, we probed its structural fusion with synthetic RXR modulator scaffolds, which had profound effects on agonist activity and remarkably boosted potency of an oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement of the acrylic acid to overcome its pan-assay interference compounds (PAINS) character enabled the development of a highly optimized RXR agonist chemical probe.
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| http://dx.doi.org/10.1021/acs.jmedchem.3c01435 | DOI Listing |
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