Abstract
Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aza Compounds / chemistry*
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Aza Compounds / pharmacokinetics
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Aza Compounds / pharmacology*
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Cell Proliferation / drug effects
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Cells, Cultured
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Diabetes Mellitus, Type 1 / drug therapy*
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Diabetes Mellitus, Type 1 / metabolism
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Dyrk Kinases
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Humans
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Insulin Secretion / drug effects
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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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Male
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Mice
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Molecular Docking Simulation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
Substances
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6-azaindole
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Aza Compounds
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Hypoglycemic Agents
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Indoles
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases