Structural Modification of the Natural Product Valerenic Acid Tunes RXR Homodimer Agonism

Retinoid X receptors (RXR) are ligand-sensing transcription factors with a unique role in nuclear receptor signaling as universal heterodimer partners. RXR modulation holds potential in cancer, neurodegeneration and metabolic diseases but adverse effects of RXR activation and lack of selective modulators prevent further exploration as therapeutic target. The natural product valerenic acid has been discovered as RXR agonist with unprecedented preference for RXR subtype and homodimer activation. To capture structural determinants of this activity profile and identify potential for optimization, we have studied effects of structural modification of the natural product on RXR modulation and identified an analogue with enhanced RXR homodimer agonism. Valerenic acid is an RXR agonist with unique subtype and homodimer preference. We have studied the impact of structural modification of the natural product on RXR modulation and identified an analogue exhibiting enhanced and selective RXR homodimer activation.image

Automated summary

This study discovered a novel selective RXR agonist, valerenic acid, which exhibits unique subtype and homodimer specificity. Through structural modification of this natural product, an analogue with enhanced activity was identified.