ArticleChemistry & biology2012
HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.
Article in Chemistry & biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- A whole-animal phenotypic drug screen identifies suppressors of atherogenic lipoproteins.eLife · 2026Article
- Stomach at the crossroads: nuclear receptor signaling at the interface between what we are and what we eat.Physiological reviews · 2026Review
- Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export.The EMBO journal · 2026Article
- The role of HNF4α in adenocarcinoma.Biochemical Society transactions · 2026Review
- The metabolic dysfunction-associated steatohepatitis (MASH) drug resmetirom exhibits broad nuclear receptor activity with minimal functional impact.Scientific reports · 2026Article
- Article
- Opposing lineage specifiers induce a protumor hybrid identity state in lung adenocarcinoma.Genes & development · 2025Article
- Mutational landscapes of HNF MODY gene products display a wide distribution with functional implications.Endocrine connections · 2025Review
- Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.ACS pharmacology & translational science · 2025Article
- Stress-induced mucin 13 reductions drive intestinal microbiome shifts and despair behaviors.Brain, behavior, and immunity · 2024Article
- High-Throughput Methods for the Discovery of Small Molecule Modulators of Pancreatic Beta-Cell Function and Regeneration.Assay and drug development technologies · 2024Review
- Targeting nuclear receptors for NASH/MASH: From bench to bedside.Liver research (Beijing, China) · 2024Article
- Article
- Targeted Activation of HNF4α by AMPK Inhibits Apoptosis and Ameliorates Neurological Injury Caused by Cardiac Arrest in Rats.Neurochemical research · 2023Article
- HNF4α in Hepatocyte Health and Disease.Seminars in liver disease · 2023Review
- Structural insights into the HNF4 biology.Frontiers in endocrinology · 2023Review
- Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine.Frontiers in endocrinology · 2023Review
- Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells.Journal of medicinal chemistry · 2022Article
- Review
- Long-term oral administration of an HNF4α agonist prevents weight gain and hepatic steatosis by promoting increased mitochondrial mass and function.Cell death & disease · 2022Article
Corrections and comments
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Authors and funding
24 authors.
Funding
Abstract
Hepatocyte nuclear factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic β cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.
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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.