Advancing LXR Modulation for Drug Discovery: Coregulator Profiling and the Development of Nonlipogenic ABCA1 Inducers

Abstract

The liver X receptor (LXR) is a nuclear hormone receptor (NHR) that plays a key role in regulating cholesterol transport (e.g., apoE, ABCA1), insulin signaling, and inflammation, making it a promising drug target for various diseases. However, the development of LXR agonists is often hindered by the undesirable side effect of lipogenesis, driven by the activation of genes such as SREBP1c. To mitigate this, drug discovery efforts have focused on selectively targeting LXRβ, based on the premise that LXRα, predominantly expressed in the liver, is responsible for lipogenesis. Despite these efforts, LXRβ-selective agonists have not yielded successful clinical outcomes. This study presents the development of precision coregulator recruitment TR-FRET (pCRT) assays to classify LXR modulators. By evaluating both coactivator and corepressor recruitment, the pCRT assays generate distinct coregulator profiles for each LXR ligand. These profiles offer valuable insights into the lipogenic versus nonlipogenic properties of LXR ligands. The work expands the characterization of LXR ligands beyond simple binding assays, providing a more comprehensive understanding. Additionally, the profiling system was used to assess optimized nonlipogenic ABCA1 inducers (NLAIs), which showed improved ABCA1 expression. These NLAIs also demonstrated better solubility and metabolic stability compared to previously reported NLAIs.