Discovery of Novel Forkhead Box O1 Inhibitors for Treating Type 2 Diabetes: Improvement of Fasting Glycemia in Diabetic db/db Mice

Abstract

Excessive hepatic glucose production through the gluconeogenesis pathway is partially responsible for the elevated glucose levels observed in patients with type 2 diabetes mellitus (T2DM). The forkhead transcription factor forkhead box O1 (Foxo1) plays a crucial role in mediating the effect of insulin on hepatic gluconeogenesis. Here, using a db/db mouse model, we demonstrate the effectiveness of Foxo1 inhibitor, an orally active small-molecule compound, as a therapeutic drug for treating T2DM. Using mass spectrometric affinity screening, we discovered a series of compounds that bind to Foxo1, identifying among them the compound, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (AS1842856), which potently inhibits human Foxo1 transactivation and reduces glucose production through the inhibition of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase mRNA levels in a rat hepatic cell line. Oral administration of AS1842856 to diabetic db/db mice led to a drastic decrease in fasting plasma glucose level via the inhibition of hepatic gluconeogenic genes, whereas administration to normal mice had no effect on the fasting plasma glucose level. Treatment with AS1842856 also suppressed an increase in plasma glucose level caused by pyruvate injection in both normal and db/db mice. Taken together, these findings indicate that the Foxo1 inhibitor represents a new class of drugs for use in treating T2DM.

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…6, B and C). Subsequently, the specific FOXO1 inhibitor AS1842856, which prevents Ser-256 phosphorylation, was added to cells during 0.1% FBS starvation (42). Whereas 0.1% FBS resulted in the expected loss of D2 activity, treatment with AS1842856 not only reversed this but increased D2 activity above baseline levels (Fig.…”

Identification of direct forkhead box O1 targets involved in palmitate-induced apoptosis in clonal insulin-secreting cells using chromatin immunoprecipitation coupled to DNA selection and ligation

“…It has been reported that FOXO1 inhibitors drastically decreased plasma glucose levels in db/db mice [37,38] and suggested that FOXO1 might be a potential target for treatment of type 2 diabetes mellitus. However, the expression of the above-mentioned targets of FOXO1 in pancreatic islets of db/db mice is poorly understood.…”

Revealing the potency of Annona muricata leaves extract as FOXO1 inhibitor for diabetes mellitus treatment through computational study

“…In vitro administration of AS1842856 on the hepatic cell line was proved to cause a decrease in glucose production. The result of the in vivo study from the AS1842856 administration in DM mice was proven to reduce glucose level of the fasting blood (Nagashima et al 2010).…”

“…The inhibition of the FOXO1 protein active side was proved to be capable of inhibiting MIN6 cell apoptosis that was induced by palmitic acid (Martinez et al 2008). Nagashima et al (2010) proved that the inhibition of the FOXO1 protein activity in the nucleus causes suppression to the gluconeogenesis process in the liver that increases insulin sensitivity in the peripheral tissues and liver of DM mice. Another study conducted by Talchai et al (2012) proved that FOXO1 protein can affect the de-differentiation process of pancreatic b cell.…”

“…While FOXO1 receptor, that was the inhibitor, was obtained from the data bank (http://www.rcsb.org/pdb/ home/home.do) server by ID 3CO6. Inhibitor reference that can inhibit the activity of FOXO1 proteins was taken from calbiochem by CID AS1842856 (Nagashima et al 2010). Furthermore, the docking process was performed by using PyRx program (Autodock vina) (Dallakyan and Olson 2015).…”