Novel Sulfonanilide Inhibitors of SHIP2 Enhance Glucose Uptake into Cultured Myotubes

A series of substituted sulfonanilide analogs were
prepared and evaluated as novel potent inhibitors of SH2 domaincontaining
inositol polyphosphate 5′-phosphatase 2 (SHIP2).
SHIP2 has been shown to be a new attractive target for the
treatment of insulin resistance in type 2 diabetes mellitus (T2D),
which can lead to life-threatening diabetic kidney disease (DKD).
Amongst the synthesized compounds, the two most promising
candidates, 10 and 11, inhibited SHIP2 significantly. Additionally,
these compounds induced Akt activation in a dose-dependent
manner, increased the presence of glucose transporter 4 at the
plasma membrane, and enhanced glucose uptake in cultured
myotubes in vitro at lower concentrations than metformin, the most widely used antidiabetic drug. These results show that the novel
SHIP2 inhibitors have insulin sensitizing capacity and provide prototypes for further drug development for T2D and DKD.