GNF-4877

GNF-4877 is an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a) and glycogen synthase kinase 3ß (Gsk3ß; IC₅₀s = 6 and 16 nM, respectively, for the mouse enzymes).¹ It is selective for Dyrk1a and Gsk3ß over a panel of 57 kinases but does inhibit 10 other kinases at 1 µM. GNF-4877 increases the proliferation of R7T1 mouse pancreatic ß-cells and primary human pancreatic ß-cells (EC₅₀s = 0.66 and 0.54 µM, respectively). It increases the number of islet and ß-cells and the levels of total DNA and ATP in primary human islet cells when used at a concentration of 2 µM. GNF-4877 (50 mg/kg twice per day) increases the proliferation of transplanted primary human islet cells and decreases the levels of blood glucose in mice. It reduces the levels of blood glucose in an oral glucose tolerance test (OGTT) in a transgenic RIP-DTA mouse model of type I diabetes when administered at a dose of 50 mg/kg twice per day. GNF-4877 also increases the mass of, and levels of insulin in, pancreatic ß-cells in the same mice.

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1. Shen, W., Taylor, B., Jin, Q., et al. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat. Commun. 6:8372, (2015).