School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
Bioorg Chem. 2018 Dec;81:264-269. doi: 10.1016/j.bioorg.2018.08.011. Epub 2018 Aug 12.
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 (K = 53 µM) and DUSP9 (K = 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.
几种蛋白酪氨酸磷酸酶（PTPs）通过 siRNA 被研究以破坏胰岛素信号通路，从而确定潜在的抗糖尿病靶点。在 3T3-L1 前脂肪细胞中，单独敲低 PTPN9 和 DUSP9 分别增加了 AMPK 的磷酸化，并且，同时敲低两者会协同性地增加 AMPK 的磷酸化。接下来，筛选了 658 种天然产物以鉴定同时抑制 PTPN9 和 DUSP9 的双重抑制剂。基于化合物的选择性和抑制效力，选择白果内酯（GA）作为进一步研究的潜在抗糖尿病药物候选物。GA 在体外抑制 PTPN9（K = 53 µM）和 DUSP9（K = 2.5 µM）的酶活性，并导致分化的 C2C12 肌肉细胞和 3T3-L1 脂肪细胞中葡萄糖摄取显著增加。此外，GA 增加了 3T3L1 脂肪细胞中 AMPK 的磷酸化。在这项研究中，GA 作为 PTPN9 和 DUSP9 的双重靶向抑制剂，通过激活 AMPK 信号通路增加了 3T3L1 和 C2C12 细胞中的葡萄糖摄取。这些结果强烈表明 GA 可用于治疗 2 型糖尿病。
