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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / drug effects
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Cell Line
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Drug Evaluation, Preclinical
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Gene Expression / drug effects
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Glucagon-Secreting Cells / cytology
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Glucagon-Secreting Cells / drug effects*
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Glucagon-Secreting Cells / metabolism*
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Humans
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Insulin / biosynthesis*
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Mice
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Molecular Structure
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Quinolones / chemistry
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Quinolones / pharmacology*
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RNA Interference
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Ribosomal Protein S6 Kinases / antagonists & inhibitors
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Ribosomal Protein S6 Kinases / genetics
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Tissue Culture Techniques
Substances
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BRD 7389
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Insulin
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Protein Kinase Inhibitors
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Quinolones
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Ribosomal Protein S6 Kinases