Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta) with cellular activity of promoting glucose uptake
文献类型：期刊论文
| 作者 | Zhang, Peng1; Li, Shufen2; Gao, Yang1; Lu, Wenbo1; Huang, Ke1; Ye, Deyong1; Li, Xi2; Chu, Yong1,3 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2014-12-15 |
| 卷号 | 24期号:24页码:5639-5643 |
| ISSN号 | 0960-894X |
| 关键词 | GSK-3 beta Substrate competitive Allosteric Benzothiazinones Anti-diabetes |
| DOI | 10.1016/j.bmcl.2014.10.078 |
| 文献子类 | Article |
| 英文摘要 | Glycogen synthase kinase 3 beta (GSK-3 beta) plays a key role in insulin metabolizing pathway and therefore inhibition of the enzyme might provide an important therapeutic approach for treatment of insulin resistance and type 2 diabetes. Recently, discovery of ATP noncompetitive inhibitors is gaining importance not only due to their generally increased selectivity but also for the potentially subtle modulation of the target. These kinds of compounds include allosteric modulators and substrate competitive inhibitors. Here we reported two benzothiazinone compounds (BTO), named BTO-5h (IC50 = 8 mu M) and BTO-5s (IC50 = 10 mu M) as novel allosteric modulator and substrate competitive inhibitor of GSK-3 beta, respectively. Their different action modes were proved by kinetic experiments. Furthermore, BTO-5s was selected to check the kinases profile and showed little or even no activity to a panel of ten protein kinases at 100 mu M, indicating it has good selectivity. Docking studies were performed to give suggesting binding modes which can well explain their impacts on the enzyme. Moreover, cell experiments displayed both compounds reduced the phosphorylation level of glycogen synthase in an intact cell, and greatly enhanced the glucose uptake in both HpG2 and 3T3-L1 cells. All of these results suggested BTO-5s and BTO-5h maybe have potentially therapeutic value for anti-diabetes. The results also offer a new scaffold for designing and developing selective inhibitors with novel mechanisms of action. (C) 2014 Elsevier Ltd. All rights reserved. |
| WOS关键词 | ALZHEIMERS-DISEASE ; GSK3 INHIBITORS ; SELECTIVE-INHIBITION ; INSULIN ; NEURODEGENERATION ; PHOSPHORYLATION ; IDENTIFICATION ; INFLAMMATION ; CANCER ; MODEL |
| 资助项目 | National Natural Science Foundation of China[81373275] ; National Natural Science Foundation of China[81270954] ; State Key Laboratory of Drug Research[SIMM1302KF-11] ; Shanghai Committee of Science and Technology of China[10ZR1401800] ; Shanghai Rising Star Program[13QH1400800] ; Shanghai New Excellent Medicine Talents Program[XYQ2011037] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| WOS记录号 | WOS:000345581300019 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276801]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Li, Xi |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Dept Med, Shanghai 201203, Peoples R China; 2.Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Key Lab Mol Med,Minist Educ, Shanghai 200032, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Peng,Li, Shufen,Gao, Yang,et al. Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta) with cellular activity of promoting glucose uptake[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2014,24(24):5639-5643. |
| APA | Zhang, Peng.,Li, Shufen.,Gao, Yang.,Lu, Wenbo.,Huang, Ke.,...&Chu, Yong.(2014).Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta) with cellular activity of promoting glucose uptake.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,24(24),5639-5643. |
| MLA | Zhang, Peng,et al."Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta) with cellular activity of promoting glucose uptake".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 24.24(2014):5639-5643. |
入库方式： OAI收割
来源：上海药物研究所
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