Small-molecule Inducers of Insulin Expression in Pancreatic Alpha-Cells

Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15099-104. doi: 10.1073/pnas.1010018107. Epub 2010 Aug 9.

Abstract

High-content screening for small-molecule inducers of insulin expression identified the compound BRD7389, which caused alpha-cells to adopt several morphological and gene expression features of a beta-cell state. Assay-performance profile analysis suggests kinase inhibition as a mechanism of action, and we show that biochemical and cellular inhibition of the RSK kinase family by BRD7389 is likely related to its ability induce a beta-cell-like state. BRD7389 also increases the endocrine cell content and function of donor human pancreatic islets in culture.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Line
  • Drug Evaluation, Preclinical
  • Gene Expression / drug effects
  • Glucagon-Secreting Cells / cytology
  • Glucagon-Secreting Cells / drug effects*
  • Glucagon-Secreting Cells / metabolism*
  • Humans
  • Insulin / biosynthesis*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Mice
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • RNA Interference
  • Ribosomal Protein S6 Kinases / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases / genetics
  • Tissue Culture Techniques

Substances

  • BRD 7389
  • Insulin
  • Protein Kinase Inhibitors
  • Quinolones
  • Ribosomal Protein S6 Kinases