Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A li Show more
Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor. Show less
Classically, activated transcription by nuclear receptors (NRs) is due to a ligand-induced switch from corepressor- to coactivator-bound states. However, coactivators and corepressors recognize overla Show more
Classically, activated transcription by nuclear receptors (NRs) is due to a ligand-induced switch from corepressor- to coactivator-bound states. However, coactivators and corepressors recognize overlapping surfaces of liganded and unliganded NRs, respectively. Here we show that, at sufficiently high concentration, the NR corepressor (NCoR) influences the activity of the liver X receptor (LXR) even in the presence of a potent full agonist that destabilizes NCoR binding. Partial agonist ligands that less effectively dissociate NCoR from LXR are even more sensitive to NCoR levels, in a target gene-selective manner. Thus, differential recruitment of NCoR is a major determinant of partial agonism and selective LXR modulation of target genes. Show less
The liver X receptors LXR alpha and LXR beta are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Seminal studies with genetic and chemical tools were in Show more
The liver X receptors LXR alpha and LXR beta are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Seminal studies with genetic and chemical tools were instrumental in the elucidation of cholesterol metabolism, gluconeogenesis, inflammation, and lipogenesis as signaling pathways that are controlled by the LXRs. First generation non-steroidal LXR agonists show beneficial effects in multiple animals models of human disease yet have not progressed in the clinic due to deleterious side effects in the liver. Numerous reports have appeared in the the recent literature that disclose new LXR signaling pathways and the identification of novel LXR chemotypes that may show improved therapeutic indices. This review will provide a brief historical perspective but will primarily focus on recent advances in LXR biology and chemistry. Show less