Small-molecule inducers of insulin expression in pancreatic α-cells

High-content screening for small-molecule inducers of insulin expression identified the compound BRD7389, which caused α-cells to adopt several morphological and gene expression features of a β-cell state. Assay-performance profile analysis suggests kinase inhibition as a mechanism of action, and we...

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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (34), p.15099-15104
Hauptverfasser:	Fomina-Yadlin, Dina, Kubicek, Stefan, Walpita, Deepika, Dančik, Vlado, Hecksher-Sørensen, Jacob, Bittker, Joshua A, Sharifnia, Tanaz, Shamji, Alykhan, Clemons, Paul A, Wagner, Bridget K, Schreiber, Stuart L
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antibodies Beta cells Biochemistry Biological Sciences Cell Differentiation - drug effects Cell Line Cell lines Cultured cells Drug Evaluation, Preclinical Endocrine cells Exocrine cells Gene Expression - drug effects Glucagon-Secreting Cells - cytology Glucagon-Secreting Cells - drug effects Glucagon-Secreting Cells - metabolism Humans Insulin Insulin - biosynthesis Insulin-Secreting Cells - cytology Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - metabolism Islet cells Islets of Langerhans - drug effects Islets of Langerhans - metabolism Mice Molecular Structure Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Quinolones - chemistry Quinolones - pharmacology Ribosomal Protein S6 Kinases - antagonists & inhibitors Ribosomal Protein S6 Kinases - genetics RNA Interference Tissue Culture Techniques Type 1 diabetes mellitus
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Beschreibung
Zusammenfassung:	High-content screening for small-molecule inducers of insulin expression identified the compound BRD7389, which caused α-cells to adopt several morphological and gene expression features of a β-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 β-cell-like state. BRD7389 also increases the endocrine cell content and function of donor human pancreatic islets in culture.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1010018107