6-Azaindole GNF2133 as DYRK1A Inhibitor for Promoting ?-Cell Proliferationv
Abstract
Yahu A Liu
Either type I or type II diabetes results from insufficient pancreatic β-cell mass or function. Dual specificity
tyrosine-regulated kinase 1A (DYRK1A) plays a key role in pancreatic β-cell proliferation. Hence,
inhibition of DYRK1A to regenerate functional insulin-producing β-cells could be an approach toward
diabetes intervention. Through medicinal chemistry optimization of an initial hit, we identified DYRK1A
inhibitor 6-azaindole GNF2133 which demonstrated significant dose-dependent glucose disposal capacity
and insulin secretion in response to GPAIS challenge in RIP-DTA mice. The work offers a potential to
treat diabetes with oral therapies by restoring β???cell mass, insulin content and glycemic control. Either
type I or type II diabetes results from insufficient pancreatic β-cell mass or function. Dual specificity
tyrosine-regulated kinase 1A (DYRK1A) plays a key role in pancreatic β-cell proliferation. Hence,
inhibition of DYRK1A to regenerate functional insulin-producing β-cells could be an approach toward
diabetes intervention. Through medicinal chemistry optimization of an initial hit, we identified DYRK1A
inhibitor 6-azaindole GNF2133 which demonstrated significant dose-dependent glucose disposal capacity
and insulin secretion in response to GPAIS challenge in RIP-DTA mice. The work offers a potential to treat
diabetes with oral therapies by restoring β???cell mass, insulin content and glycemic control.
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