期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 136, 期 -, 页码 348-359出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.05.007
关键词
Type 2 diabetes; PTP1B inhibition; Selectivity; Competitive; Cellular activity
资金
- National Natural Science Foundation of China [41506169]
- Key research and development project of Shandong province [2015GSF115029, 2016ZDJS07A13, 2016GSF115002, 2016GSF201193]
- Key Research Program of Frontier Sciences, CAS [QYZDB-SSW-DQC014]
- China Postdoctoral Science Foundation [2015KY11-4]
- Project of Discovery, Evaluation and Transformation of Active Natural Compounds
- Strategic Biological Resources Service Network Programme of Chinese Academy of Sciences [ZSTH-026]
- NSFC-Shandong Joint Fund for Marine Science Rearch Centers [U1606403]
- Scientific and Technological Innovation Project - Qingdao National Laboratory for Marine Science and Technology [2015ASKJ02]
- Qingdao National Laboratory for Marine Science and Technology [2015ASTP]
- National Program for Support of Top-notch Young Professionals
- Taishan scholar Youth Project of Shandong province
- Aoshan Talents Program
Protein tyrosine phosphatases 1B (PTP1B) is a promising and validated therapeutic target to effectively treat T2DM and obesity. However, the development of charged PTP1B inhibitors was restricted due to their low cell permeability and poor bioavailability. Based on active natural products, two series of uncharged catechol derivatives were identified as PTP1B inhibitors by targeting a secondary aryl phosphate-binding site as well as the catalytic site. The most potent inhibitor 22 showed an IC50 of 0.487 mu M against PTP1B and strong selectivity (27-fold) over TCPTP. Kinetic studies were also performed that 22 act as a competitive PTP1B inhibitor. The treatment of C2C12 myotubes with 22 markedly increased the phosphorylation levels of IR beta, Akt and IRS1 phosphorylation. The similarity of its action profiling with that produced by insulin suggested its potential as a new non-insulin-dependent drug candidate. (C) 2017 Elsevier Masson SAS. All rights reserved.
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