New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH‑1

Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is a lipid-regulated transcription factor and an
important drug
target for several liver diseases. Advances toward LRH-1 therapeutics
have been driven recently by structural biology, with fewer contributions
from compound screening. Standard LRH-1 screens detect compound-induced
interaction between LRH-1 and a transcriptional coregulator peptide,
an approach that excludes compounds that regulate LRH-1 through alternative
mechanisms. Here, we developed a FRET-based LRH-1 screen that simply
detects compound binding to LRH-1, applying it to discover 58 new
compounds that bind the canonical ligand-binding site in LRH-1 (2.5%
hit rate), also supported by computational docking. Four independent
functional screens identified 15 of these 58 compounds to also regulate
LRH-1 function in vitro or in living cells. Although one of these
15 compounds, abamectin, directly binds LRH-1 and regulates full-length
LRH-1 in cells, abamectin failed to regulate the isolated ligand-binding
domain in standard coregulator peptide recruitment assays using PGC1α,
DAX-1, or SHP. Abamectin treatment of human liver HepG2 cells selectively
regulated endogenous LRH-1 ChIP-seq target genes and pathways associated
with known LRH-1 functions in bile acid and cholesterol metabolism.
Thus, the screen reported here can discover compounds not likely to
have been identified in standard LRH-1 compound screens but which
bind and regulate full-length LRH-1 in cells.