GNF4877 is a potent DYRK1A and GSK3β inhibitor with IC₅₀s of 6?nM and 16?nM, respectively, which leads to blockade of nuclear factor of activated T-cells (NFATc) nuclear export and increased β-cell proliferation (EC₅₀ of 0.66?μM for mouse β (R7T1) cells)^[1].

High glucose concentrations and glucokinase activators (GKAs) increase Ca²⁺ signalling in β-cells, and increase intracellular Ca²⁺ leads to activation of calcineurin and nuclear translocation of NFATc proteins. Indeed, concentrations of GNF4877 ((0.1?μM, 0.3?μM) well below the EC₅₀ for β-cell proliferation are able to induce proliferation in the presence of high glucose or pharmacological activators of glucokinase. Finally, increasing intracellular Ca²⁺ with glibenclamide (a sulfonylurea receptor 1 inhibitor) or Bay K8644 (an L-type Ca²⁺ channel activator) show additive activity with GNF4877^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

GNF4877 (50 mg/kg; oral gavage; twice a day; for 15 days; double transgenic RIP-DTA male mice) treatment induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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• [1]. Shen W, et al. Inhibition of DYRK1A and GSK3β induces human β-cell proliferation. Nat Commun. 2015 Oct 26;6:8372.  [Content Brief]