Progress and challenges of selective Farnesoid X Receptor modulation

Abstract

Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism. In addition, FXR activation has been shown to limit the inflammatory response. The central role of FXR in various aspects of metabolism and inflammation makes FXR an attractive drug target for several diseases, such as obesity, metabolic syndrome, non-alcoholic steatohepatitis, cholestasis and chronic inflammatory diseases of the liver and intestine. However, most of the currently available compounds impact on all discovered FXR-mediated functions and may have, on top of beneficial effects, undesired biological actions depending on the disease. Therefore, research efforts are increasingly focused on the development of selective FXR modulators, i.e. selective bile acid receptor modulators (SBARMs), aimed at limiting the potential side-effects of conventional full FXR agonists upon chronic treatment. Here, we review the rationale for the design of SBARMs comprising dissociation between metabolic and inflammatory signaling, gene-selective and tissue-specific targeting. We discuss the potential structural mechanisms underlying the binding properties of dissociating ligands of FXR in light of ongoing efforts on the generation of dissociated ligands for otxher nuclear receptors, as well as their pharmacological and therapeutic potential.

Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

“…Many attempts to overcome these problems in combination with crystallographic studies and virtual screening campaigns have given rise to several series of derivatives, and recent progress has been made with high-affinity binding and agonist activity of structurally-diverse, natural (epigallocatechin-3-gallate, cafestol) or (semi)synthetic (GSK2324; WAY-36245; AGN29; PX20606) molecules toward FXRα. In contrast, only a limited number of FXRα antagonists (guggulsterone, stigmasterol, AGN31, AGN34) have been described in the literature [ 104 , 105 ]. While these latter compounds may be useful pharmacological tools to extend the understanding of FXRα functions, complementary studies are required to further validate the potency of these agents as clinic therapeutic modulators of FXRα in human disabilities.…”

Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport

“…Moreover, differential expression of co-regulatory proteins in these cell types might lead to tissue-specific target gene expression. Several intestinal-specific FXR agonists are already known (fexaramine, TC-100, ivermectin, ECGC) and are suggested to be safer for the treatment of metabolic syndrome-related diseases than systemic FXR agonists [8].…”

“…The therapeutic potential of FXR lies in the treatment of cholestatic liver diseases, hypercholesterolemia, hypertriglyceridemia, nonalcoholic steatohepatitis, and type 2 diabetes mellitus [7]. Of note, 1 FXR agonist, obeticholic acid (Ocaliva), has already been approved in the U. S. and Europe in a fast track procedure for the treatment of primary biliary cholangitis (PBC) [8]. Despite its beneficial impact in the therapy of PBC, obeticholic acid has several adverse effects, such as pruritus, fatigue, and gastrointestinal symptoms.…”

“…High affinity full agonists of FXR activate the whole plethora of FXR target genes and are therefore more likely to elicit undesirable effects. Therefore, increasing focus is directed at the identification and development of selective bile acid receptor modulators (SBARM) that act in a tissue-or gene-specific manner with the ultimate goal to design FXR agonists for specific therapeutic purposes (reviewed in [8]). This aim is very challenging as the mechanisms underlying gene-and tissue-selectivity are still being elucidated.…”

“…This aim is very challenging as the mechanisms underlying gene-and tissue-selectivity are still being elucidated. Several hypotheses about how to achieve selectivity have been proposed, including differential cofactor or DNA binding, transactivation versus transrepression, and binding of ligands to allosteric pockets (S2 pocket) [8].…”