Several protein tyrosine phosphatases (PTPs) that disrupt the insulin-signaling pathway were investigated by siRNAs to identify potential antidiabetic targets. Individual knockdown of PTPN9 and DUSP9 in 3T3-L1 preadipocytes increased AMPK phosphorylation, respectively, and furthermore, concurrent knockdown of both PTPN9 and DUSP9 synergistically increased AMPK phosphorylation. Next, 658 natural products were screened to identify dual inhibitors of both PTPN9 and DUSP9. Based on the selectivity and inhibition potency of the compounds, ginkgolic acid (GA) was selected for further study as a potential antidiabetic drug candidate. GA inhibited the enzymatic activity of PTPN9 (Ki = 53 µM) and DUSP9 (Ki = 2.5 µM) in vitro and resulted in a significant increase of glucose-uptake in differentiated C2C12 muscle cells and 3T3-L1 adipocytes. In addition, GA increased phosphorylation of AMPK in 3T3L1 adipocytes. In this study, GA as a dual targeting inhibitor of PTPN9 and DUSP9 increased glucose uptake in 3T3L1 and C2C12 cells by activating the AMPK signaling pathway. These results strongly suggest GA could be used as a therapeutic candidate for type 2 diabetes.
Keywords: DUSP9; Dual-targeting inhibitor; Ginkgolic acid; Glucose-uptake; PTPN9; Protein tyrosine phosphatases; Type 2 diabetes.
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