Small-molecule inducers of insulin expression in pancreatic alpha-cells.
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.
Fomina-Yadlin
Dina
D
Howard Hughes Medical Institute, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142.
Kubicek
Stefan
S
Walpita
Deepika
D
Dancik
Vlado
V
Hecksher-Sørensen
Jacob
J
Bittker
Joshua A
JA
Sharifnia
Tanaz
T
Shamji
Alykhan
A
Clemons
Paul A
PA
Wagner
Bridget K
BK
Schreiber
Stuart L
SL
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
C552253:BRD 7389; D007328:Insulin; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D019893:Ribosomal Protein S6 Kinases