Year: 2023
Type: article
Abstract: ) 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.
Source: ACS Chemical Biology
Institutions: Vanderbilt University Medical Center, Vanderbilt University
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
Funders: American Cancer Society, Vanderbilt University, National Institutes of Health, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Vanderbilt Institute of Chemical Biology, School of Medicine, Vanderbilt University, Army Research Office
Awards: A new kinase inhibitor for glioblastoma, G187284979, G3433274139, G5853943267, Full-length LRH-1 structural regulation, G7603387250, G9000052735, Multidisciplinary Training in Molecular Endocrinology, G9000251729, Cancer Center Support Grant, Vanderbilt Diabetes Research Center, VGM: Vanderbilt Genomic Medicine Training Program, Research Training in Diabetes and Endocrinology
OpenAlex ID: W4366352190