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The bile-acid sensing nuclear farnesoid X receptor (FXR) is an attractive target for the treatment of hepatic and metabolic diseases, but application of this chemotherapeutic concept remains limited due to adverse effects of FXR activation observed in clinical trials. To elucidate the mechanistic basis of FXR activation at the molecular level, we have systematically studied FXR co-regulator interactions and dimerization in response to seven chemically diverse FXR ligands. Different molecular effects on FXR activation mediated by different scaffolds were evident and aligned with characteristic structural changes within the ligand binding domain of FXR. A partial FXR agonist acted mainly through co-repressor displacement from FXR and caused an FXR-regulated gene expression pattern markedly differing from FXR agonist effects. These results suggest selective modulation of FXR dimerization and co-regulator interactions for different ligands, offering a potential avenue for the design of gene- or tissue-selective FXR modulators.

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.