AS1842856 is a specific Foxo1 inhibitor with IC50 of 30 nM. AS1842856 effectively inhibits autophagy[1]. AS1842856 only reduces Foxo1 activity by binding to Foxo1 without affecting its transcription and protein expression[2].

AS1842856 (0.1 μM) inhibits 70% of Foxo1-mediated promoter activity. AS1842856 may inhibit the activity of endogenous G6Pase and PEPCK by reducing the mRNA levels of G6Pase and PEPCK, which may inhibit the production of glucose in Fao cells[1].

In db/db mutant mice with diabetes, oral administration of AS1842856 can inhibit the genes related to gluconeogenesis of the liver, resulting in a large decrease in fasting blood glucose. In normal mice and db/db mice, treatment with AS1842856 can also suppress the increase in blood glucose levels caused by injection of pyruvate[1].

References:

[1]. Nagashima T, et al. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. Mol Pharmacol, 2010, 78(5): 961-70.

[2]. He J, et al. The resistant effect of SIRT1 in oxidative stress-induced senescence of rat nucleus pulposus cell is regulated by Akt-FoxO1 pathway. Biosci Rep, 2019, 39(5).