[논문]Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance

Yoon, Sun-Young; Kang, Hyo Jin; Ahn, Dohee; Hwang, Ji Young; Kwon, Se Jeong; Chung, Sang J.

doi:10.1016/j.bioorg.2019.103087

Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance

Bioorganic chemistry, v.90, 2019년, pp.103087 -

Yoon, Sun-Young (School of Pharmacy, Sungkyunkwan University) , Kang, Hyo Jin (Department of Chemistry, Dongguk University) , Ahn, Dohee (School of Pharmacy, Sungkyunkwan University) , Hwang, Ji Young (School of Pharmacy, Sungkyunkwan University) , Kwon, Se Jeong (School of Pharmacy, Sungkyunkwan University) , Chung, Sang J. (School of Pharmacy, Sungkyunkwan University)

Abstract ▼ AI-Helper

Abstract Natural products as antidiabetic agents have been shown to stimulate insulin signaling via the inhibition of the protein tyrosine phosphatases relevant to insulin resistance. Previously, we have identified PTPN9 and DUSP9 as potential antidiabetic targets and a multi-targeting natural product thereof. In this study, knockdown of PTPN11 increased AMPK phosphorylation in differentiated C2C12 muscle cells by 3.8 fold, indicating that PTPN11 could be an antidiabetic target. Screening of a library of 658 natural products against PTPN9, DUSP9, or PTPN11 identified chebulinic acid (CA) as a strong allosteric inhibitor with a slow cooperative binding to PTPN9 (IC50 = 34 nM) and PTPN11 (IC50 = 37 nM), suggesting that it would be a potential antidiabetic candidate. Furthermore, CA stimulated glucose uptake and resulted in increased AMP-activated protein kinase (AMPK) phosphorylation. Taken together, we demonstrated that CA increased glucose uptake as a dual inhibitor of PTPN9 and PTPN11 through activation of the AMPK signaling pathway. These results strongly suggest that CA could be used as a potential therapeutic candidate for the treatment of type 2 diabetes. Highlights PTPN11 (also called SHP-2) was identified as a new antidiabetic target. Chebulinic acid was a dual allosteric inhibitor of PTPN9 and PTPN11. Chebulinic acid stimulated glucose uptake through activation of the AMPK pathway. Chebulinic acid could be a potential therapeutic agent to treat type 2 diabetes. Graphical abstract [DISPLAY OMISSION]

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Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance

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Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance

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