Identification and characterization of potent and selective inhibitors targeting protein tyrosine phosphatase 1B (PTP1B) |
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| Authors: | Jia Jin Xiaoqing Ye Derrick Boateng Kaili Dai Fei Ye Pengfei Du Han Yu |
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| Affiliation: | 1. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China;2. Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Hangzhou 310018, China;3. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materta Medica, Chinese Academy of Sciences, Shanghai 201203, China;4. Department of Endocrinology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China;5. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China |
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| Abstract: | Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin and leptin signaling. The development of small molecular inhibitors targeting PTP1B has been validated as a potential therapeutic strategy for Type 2 diabetes (T2D). In this work, we have identified a series of compounds containing dihydropyridine thione and particular chiral structure as novel PTP1B inhibitors. Among those, compound 4b showed moderate activity with IC50 value of 3.33 μM and meanwhile with good selectivity (>30-fold) against TCPTP. The further MOA study of PTP1B demonstrated that compounds 4b is a substrate-competitive inhibitor. The binding mode analysis suggested that compound 4b simultaneously occupies the active site and the second phosphotyrosine (pTyr) binding site of PTP1B. Furthermore, the cell viability assay of compound 4b showed tolerable cytotoxicity in L02 cells, thus 4b may be prospectively used to further in vivo study. |
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| Keywords: | Corresponding authors. PTP1B TCPTP Type 2 diabetes Selective inhibitors Dihydropyridine thione |
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