2. Academic Validation
  3. HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter

HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter

  • Chem Biol. 2012 Jul 27;19(7):806-18. doi: 10.1016/j.chembiol.2012.05.014.
Alice Kiselyuk 1,  Seung-Hee Lee,  Suzette Farber-Katz,  Mingjun Zhang,  Sonalee Athavankar,  Tom Cohen,  Anthony B Pinkerton,  Mao Ye,  Paul Bushway,  Adam D Richardson,  Heather A Hostetler,  Mariam Rodriguez-Lee,  Li Huang,  Benjamin Spangler,  Layton Smith,  Jennifer Higginbotham,  John Cashman,  Hudson Freeze,  Pamela Itkin-Ansari,  Marcia I Dawson,  Friedhelm Schroeder,  Yong Cang,  Mark Mercola,  Fred Levine
Affiliations

Affiliation

  • 1 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
PMID: 22840769 DOI: 10.1016/j.chembiol.2012.05.014
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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