HNF4? antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.

ABSTRACT: Hepatocyte nuclear factor (HNF)4? is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic ? cells. Although fatty acids were found to occupy the HNF4? ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4? ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4? antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4? with high affinity and modulated the expression of known HNF4? 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 HNF4? raises the possibility that diseases involving HNF4?, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4? activity.

SUBMITTER: Kiselyuk A 

PROVIDER: S-EPMC3447631 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature