1. Novel Sulfonanilide Inhibitors of SHIP2 Enhance Glucose Uptake into Cultured Myotubes
- Author
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Tuomas Aleksi Tolvanen, Jette-Britt Naams, Kristiina Wähälä, Mika Erik Anthon Berg, Sanna Lehtonen, Jari Ahonen, Laura Hautala, Research Services, Doctoral Programme in Chemistry and Molecular Sciences, Department of Chemistry, Diabetes and Obesity Research Program, Doctoral Programme in Biomedicine, Sanna Lehtonen research group, Doctoral Programme in Integrative Life Science, Department of Pathology, Doctoral Programme in Drug Research, Medicum, and HUS Helsinki and Uusimaa Hospital District
- Subjects
STIMULATION ,PHOSPHATASE ,METFORMIN ,General Chemical Engineering ,Glucose uptake ,medicine.medical_treatment ,116 Chemical sciences ,030209 endocrinology & metabolism ,INPPL1 ,Pharmacology ,Article ,Sulfonanilide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,INOSITOL ,medicine ,Inositol ,Protein kinase B ,QD1-999 ,030304 developmental biology ,0303 health sciences ,Insulin ,Glucose transporter ,General Chemistry ,ASSOCIATION ,medicine.disease ,3. Good health ,Metformin ,Chemistry ,chemistry ,3121 General medicine, internal medicine and other clinical medicine ,CELLS ,PLASMA-MEMBRANE ,5'-PHOSPHATASE-2 GENE POLYMORPHISMS ,SULFONYLUREAS ,medicine.drug - Abstract
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.
- Published
- 2020