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

Alice Kiselyuk1, Seung-Hee Lee, Suzette Farber-Katz

  • 1Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

Chemistry & Biology
|July 31, 2012
PubMed

Insights

Researchers discovered synthetic antagonists for Hepatocyte nuclear factor (HNF)4α, a key regulator in metabolic homeostasis. These compounds show selective cytotoxicity to cancer cells, suggesting potential therapeutic applications for HNF4α-related diseases like diabetes and cancer.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Pharmacology

Background:

  • Hepatocyte nuclear factor (HNF)4α is a crucial regulator of gene expression in metabolic homeostasis.
  • The precise ligands and physiological role of HNF4α binding remain debated, despite fatty acids being proposed as ligands.

Purpose of the Study:

  • To identify potent synthetic antagonists of HNF4α.
  • To investigate the therapeutic potential of HNF4α modulators in diseases like diabetes and cancer.

Main Methods:

  • High-throughput screening for effectors of the human insulin promoter.
  • Assessing binding affinity of synthetic compounds to HNF4α.
  • Evaluating the modulation of HNF4α target gene expression.
  • Testing selective cytotoxicity in cancer cell lines in vitro and in vivo.

Main Results:

  • Discovery of potent synthetic HNF4α antagonists with high binding affinity.
  • Demonstrated modulation of known HNF4α target genes.
  • Selective cytotoxicity observed in cancer cell lines both in vitro and in vivo.
  • In vivo efficacy was limited by pharmacokinetic properties.

Conclusions:

  • Bioactive modulators of HNF4α have been identified.
  • Targeting HNF4α activity offers a potential therapeutic strategy for HNF4α-associated diseases, including diabetes and cancer.

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