A Dual Inhibitor of DYRK1A and GSK3β for β‐Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β‐cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β‐cell mass are less developed. Promoting β‐cell proliferation with low‐molecular‐weight inhibitors of dual‐specificity tyrosine‐regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β‐cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β‐cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high‐throughput screening campaign measuring β‐cell proliferation. Getting more cells on site: Promoting β‐cell proliferation with inhibitors of dual‐specificity tyrosine‐regulated kinase 1A (DYRK1A) offers the potential for treating diabetes patients by restoring β‐cell mass. Lead optimization of an aminopyrazine hit led to the identification of GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β).