ArticleJournal of medicinal chemistry2019
Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design.
Article in Journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Microbiome-host communication via vaccenic acid modulates LRH-1/NR5A2 activity and ameliorates metabolic liver disease.EMBO molecular medicine · 2026Article
- From hepatic to hematopoietic: LRH-1's expanding cellular repertoire to the immune system.The FEBS journal · 2026Review
- Structure-guided compound prioritization strategy for virtual screening identifies putative binders for the nuclear receptor LRH-1.bioRxiv : the preprint server for biology · 2026Article
- Exploring the Expanding Role of Nuclear Receptor LRH-1/NR5A2 in Cell Biology and Immunity.International journal of cell biology · 2026Review
- Fragment-Based Discovery of Drug-like LRH-1 Agonists.ACS medicinal chemistry letters · 2025Article
- Fatty Acid Mimetic Fragments as Liver Receptor Homologue-1 Modulators.ACS pharmacology & translational science · 2025Article
- Impact of Replicas and Simulation Length on In Silico Behaviors of a Protein Domain.Chemphyschem : a European journal of chemical physics and physical chemistry · 2025Article
- A novel heuristic of rigid docking scores positively correlates with full-length nuclear receptor LRH-1 regulation.Computational and structural biotechnology journal · 2024Article
- Liver receptor homolog-1: structures, related diseases, and drug discovery.Acta pharmacologica Sinica · 2024Review
- The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits.Protein science : a publication of the Protein Society · 2023Article
- Early Life Stress in Mice Leads to Impaired Colonic Corticosterone Production and Prolonged Inflammation Following Induction of Colitis.Inflammatory bowel diseases · 2023Article
- New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1.ACS chemical biology · 2023Article
- A phospholipid mimetic targeting LRH-1 ameliorates colitis.Cell chemical biology · 2022Article
- Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.Journal of medicinal chemistry · 2022Article
- Nuclear receptor NR5A2 negatively regulates cell proliferation and tumor growth in nervous system malignancies.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Another One Bites the Gut: Nuclear Receptor LRH-1 in Intestinal Regeneration and Cancer.Cancers · 2021Review
- Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist.Scientific reports · 2020Article
- Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.Bioorganic & medicinal chemistry letters · 2020Article
- Integrated Structural Modeling of Full-Length LRH-1 Reveals Inter-domain Interactions Contribute to Receptor Structure and Function.Structure (London, England : 1993) · 2020Article
- Development of a Versatile and Sensitive Direct Ligand Binding Assay for Human NR5A Nuclear Receptors.ACS medicinal chemistry letters · 2020Article
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14 authors at 3 institutions in 1 country.
Funding
Abstract
As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, liver receptor homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases (IBD). Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of IBD, the new agonist increases expression of LRH-1-controlled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.