Oleanolic acid and its derivatives: new inhibitor of protein tyrosine phosphatase 1B with cellular activities.
Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, a series of competitive inhibitors were optimized from oleanolic acid, a natural triterpenoid identified against PTP1B by screening libraries of traditional Chinese medicinal herbs. Modifying at 3 and 28 positions, we obtained compound 13 with a K(i) of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin.
Zhang
Yi-Nan
YN
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, 199 Guo Shou Jing Road, Shanghai 201203, China.
Zhang
Wei
W
Hong
Di
D
Shi
Lei
L
Shen
Qiang
Q
Li
Jing-Ya
JY
Li
Jia
J
Hu
Li-Hong
LH
D000818:Animals; D016466:CHO Cells; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D004365:Drugs, Chinese Herbal / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000201:enzymology
D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D007328:Insulin; D009828:Oleanolic Acid; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1