AS1949490 is a highly potent, orally bioavailable inhibitor of SHIP2 phosphatase, displaying IC50 values of 0.34 and 0.62 µM against Mouse and Human SHIP2, respectively. Its selectivity profile shows significantly weaker activity against Human SHIP1, PTEN, synaptojanin, and myotubularin, with no inhibitory effect observed at concentrations above 50 µM for these enzymes. AS1949490 enhances the phosphorylation of Akt, leading to increased glucose consumption and uptake, thereby activating the intracellular insulin signaling pathways. This mechanism underlines its potential utility in diabetes research[1].[2].
体内研究
In diabetic mice, oral administration of AS1949490 at 300 mg/kg, twice daily for 7 or 10 days, lowers plasma glucose levels and activates intracellular insulin signaling. When given once at 300 mg/kg for 8 hours to male ICR mice, the compound suppresses gluconeogenesis and the expression of genes associated with this metabolic pathway[1].
体外研究
In L6 myotubes, AS1949490 boosts insulin-induced phosphorylation of Akt at concentrations ranging from 0 to 16 μM after 15 minutes of treatment[1].
It activates glucose metabolism and augments glucose uptake activity at doses between 0 to 10 μM over 48 hours. Additionally, a 24-hour treatment with 0 to 10 μM AS1949490 reduces insulin-induced gluconeogenesis in L6 myotubes[1].
A specific up-regulation of the GLUT1 gene, indicative of stimulated glucose metabolism, was observed with a 10 μM dosage over 48 hours[2].
AS1949490 细胞实验
Cell Line
Concentration
Treated Time
Description
References
dopaminergic neurons
5 µM, 1 µM, 0.5 µM, 0.05 µM
3 days
To investigate the effect of AS1949490 on α-synuclein aggregation, results showed no significant effect at concentrations from 0.05 µM to 1 µM, while 5 µM concentration caused cell death
Biomolecules. 2022 Apr 9;12(4):563
PA-treated human podocytes
10 µM
48 h
AS1949490 failed to reduce PA-induced ROS production or apoptosis.
Sci Rep. 2017 Sep 6;7(1):10731
CD2AP−/− mouse podocytes
10 µM
24 h
AS1949490 inhibited SHIP2 activity, reduced ROS production, but further decreased PDK1 expression and aggravated apoptosis.
Sci Rep. 2017 Sep 6;7(1):10731
AS1949490 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Db/db mice
Diabetic model
Oral
300 mg/kg
Twice daily for 7 or 10 days
AS1949490 significantly lowered the plasma glucose level and improved glucose intolerance
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