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 domain-containing 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, and , inhibited SHIP2 significantly.

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake.