Novel Sulfonanilide Inhibitors of SHIP2 Enhance Glucose Uptake into Cultured Myotubes

Mika E A Berg; Jette-Britt Naams; Laura C Hautala; Tuomas A Tolvanen; Jari P Ahonen; Sanna Lehtonen; Kristiina Wähälä

doi:10.1021/acsomega.9b02944

Novel Sulfonanilide Inhibitors of SHIP2 Enhance Glucose Uptake into Cultured Myotubes

ACS Omega. 2020 Jan 14;5(3):1430-1438. doi: 10.1021/acsomega.9b02944. eCollection 2020 Jan 28.

Authors

Mika E A Berg¹, Jette-Britt Naams², Laura C Hautala², Tuomas A Tolvanen³, Jari P Ahonen¹, Sanna Lehtonen^{2

3}, Kristiina Wähälä^{4

1}

Affiliations

¹ Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland.
² Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Haartmaninkatu 3, Helsinki, 00014 Finland.
³ Department of Pathology, University of Helsinki, Haartmaninkatu 3, 00014 Helsinki, Finland.
⁴ Department of Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 3, 00014 Helsinki, Finland.

Abstract

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, 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.