Ligands of Therapeutic Utility for the Liver X Receptors

Abstract

Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRβ ligands based on the interaction energies of ligands and the important amino acid residues in the LXRβ ligand binding domain.

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

“…The selectivity of LXR ligands can be attributed to several factors, including degree of induction of genes involved in lipid transport, namely, ABCA1, ABGA1, and APOE, or of transrepression of proinflammatory genes, such as nitric oxide synthase and cyclooxygenase-2, or proinflammatory cytokines in microglia and astrocytes (47,69,70). It has further been proposed, but unproved, that GW3965 and TO901317 may bind to both isoforms with varying degrees of binding affinity (71). In our studies, in vitro assays allowed comparison of the function of agonists GW3965 and TO901317, versus the antagonist GSK2033 in RPE and choroidal endothelial cells.…”

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

“…[117]; and endogenous antagonists include arachidonic acid and its cyclooxygenase metabolites, such as PGF 2α , ursodeoxycholic acid and 5,6-epoxycholesterol [118]. TO901317 is a non-steroidal synthetic ligand of LXR that induces ABCA1 expression [116], while it is also an effective activator of the pregnane X receptor (PXR) and the farnesoid X receptor (FXR), as well as an inhibitor of RORs [77].…”

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

“…Intriguingly though, there are some reports of long-term statins usage causing ALS, which is attributed to the parallel reduction of mitochondrial antioxidant coenzyme Q10 (CoQ 10 ) by the inhibition of HMG-CoA reductase enzyme (Edwards, Star, & Kiuru, 2007 (Komati et al, 2017) for which a mitochondrial health assay approach may prove useful to implement drug screening ( Figure 2). Intriguingly though, there are some reports of long-term statins usage causing ALS, which is attributed to the parallel reduction of mitochondrial antioxidant coenzyme Q10 (CoQ 10 ) by the inhibition of HMG-CoA reductase enzyme (Edwards, Star, & Kiuru, 2007 (Komati et al, 2017) for which a mitochondrial health assay approach may prove useful to implement drug screening ( Figure 2).…”

“…Potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches. In spite of this, challenges remain in minimizing the undesirable effects of LXR activation on lipid metabolism (Komati et al, 2017) for which a mitochondrial health assay approach may prove useful to implement drug screening ( Figure 2).…”