AS 1949490 is a selective inhibitor of Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2), [1] with IC50 values of 0.34 µM and 0.62 µM to mouse and human SHIP2s, respectively [2].
SHIP2 is an intracellular phosphatase and appears to be important in insulin signaling as a negative regulator. SHIP2 has potential to act as a treatment for type 2 diabetes because of its inhibition [2].
Akt is a key enzyme to regulated insulin signaling. AS 1949490 treatment dose-dependently increased insulin-induced phosphorylation of Akt in L6 myotubes, but did not result in any associated changes in the overall level of Akt protein and the fetal bovine serum-induced phosphorylation of Akt. Treatments with AS 1949490 at several concentrations of and 1 nM insulin for 48 h, showed more consumption of glucose in the medium in a concentration-dependent manner [2].
In diabetic db/db mice, administered with AS 1949490 twice daily p.o. for 7 or 10 days significantly decreased plasma glucose (23% reduction, relative to vehicle), without affecting insulin levels, food intake or body weight. In the 10th day, treatment with AS 1949490 resulted in significant reduction in both the area under the blood glucose concentration time curve (AUC) and fasting blood glucose (37% reduction, compared with vehicle; time = -30 min) [2].
References:
[1]. Laura Beth J. McIntire, Kyu-In Lee, Belle Chang-IIeto, et al. Screening assay for small molecule inhibitors of synaptojanin 1, a synaptic phosphoinositide phosphatase. J Biomol Screen, 2014, 19(4):585-594.
[2]. A Suwa, T Yamamoto, A Sawada, et al. Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2. British Journal of Pharmacology, 2009, 158:879-887.