Deficiency in β-cell mass or function can lead to insufficient levels of insulin, resulting in hyperglycemia and diabetes. Thus, promoting β-cell proliferation to increase β-cell mass could be one approach toward diabetes intervention. We identified 6-azaindole derivatives (including GNF2133) as potent and selective DYRK1A inhibitors which were able to proliferate both rodent and human β-cells. GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose potentiated arginine-induced insulin secretion challenge in RIP-DTA mice. The work showed that DYRK1A inhibition could be one of the new avenues to beta-cell regeneration and preservation for treatment of type 1 diabetes.

6-Azaindole derivative GNF2133 as DYRK1A inhibitor for the treatment of Type 1 diabetes

ACS Fall 2021

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