Three Decades of Liver X Receptor Agonist Chemistry: Structural Motifs, Structure-activity Relationship, and...

Liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of gene expression involved in lipid metabolism, cholesterol homeostasis and inflammation. Certain modifications in endogenous LXR activity have been associated with pathological conditions and diseases. The dysregulation of LXR activity can lead to vascular and metabolic diseases, neurological degeneration and formation of malignant tumors. One of the solutions to treat the diseases or at least to slow down the progression is the development of different strategies to modulate LXR signaling for the treatment or prevention of these pathological conditions. Many researchers and pharmaceutical companies are developing selective LXR modulators to precisely control receptor activity and achieve specific pharmacological effects. The activation of LXRs has been linked to the inhibition of cell proliferation and metastasis, the promotion of apoptosis and re-differentiation of tumor cells that drives exosome release to stimulate anti-tumor immunity in certain cancer types. The main challenge is to minimize the adverse effects of LXR induction on lipid metabolism via selective activation of LXRβ isoform. Several lead compounds were identified and tested in clinical trials for few pathologies discussed above. The discovery of a potent and selective LXR ligand involves a combination of multiple steps from lead discovery, optimization, preclinical and clinical testing before getting to marketing authorization. This review offers an overview of synthetic agonists for LXRs developed over the past three decades. Though multiple investigations have been in progress, no FDA-approved LXR-targeting drug is available so far.