Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6‑Azaindole Derivative GNF2133

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).