title: Small-molecule inducers of insulin expression in pancreatic alpha-cells.
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.
authors.affiliation: Howard Hughes Medical Institute, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142.
authors.forename: Dina
authors.initials: D
authors.lastname: Fomina-Yadlin
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Deepika
authors.initials: D
authors.lastname: Walpita
authors.forename: Vlado
authors.initials: V
authors.lastname: Dancik
authors.forename: Jacob
authors.initials: J
authors.lastname: Hecksher-Sørensen
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.forename: Tanaz
authors.initials: T
authors.lastname: Sharifnia
authors.forename: Alykhan
authors.initials: A
authors.lastname: Shamji
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D046509:Tissue Culture Techniques
chemical_list: C552253:BRD 7389; D007328:Insulin; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D019893:Ribosomal Protein S6 Kinases