Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3β (GSK-3β) with cellular activity of promoting glucose uptake
Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3β (GSK-3β) with cellular activity of promoting glucose uptake
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DOI：
10.1016/j.bmcl.2014.10.078
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发表时间：
2014-12-15
影响因子：
2.7
通讯作者：
Chu, Yong
中科院分区：
文献类型：
--
作者：
Zhang, Peng;Li, Shufen;Chu, Yong
糖原合成酶激酶3 β（Glycogen synthase kinase 3 beta，GSK-3 beta）在胰岛素代谢途径中起着关键作用，因此抑制该酶可能为胰岛素抵抗和2型糖尿病的治疗提供重要的治疗途径。最近，ATP非竞争性抑制剂的发现越来越重要，这不仅是因为它们的选择性普遍增加，而且还因为对靶点的潜在微妙调节。这些种类的化合物包括变构调节剂和底物竞争性抑制剂。在这里，我们报告了两种苯并噻嗪酮化合物（BTO），命名为BTO-5 h（IC 50 = 8 μ M）和BTO-5s（IC 50 = 10 μ M），分别作为GSK-3 β的新型变构调节剂和底物竞争性抑制剂。动力学实验证明了它们的不同作用方式。此外，选择BTO-5s来检查激酶谱，并且在100 μ M下对一组10种蛋白激酶显示很少或甚至没有活性，表明其具有良好的选择性。进行了对接研究，以给出建议的结合模式，可以很好地解释它们对酶的影响。此外，细胞实验显示两种化合物降低完整细胞中糖原合酶的磷酸化水平，并大大增强HpG 2和3 T3-L1细胞中的葡萄糖摄取。这些结果提示BTO-5s和BTO-5 h可能具有潜在的抗糖尿病治疗价值。这些结果也为设计和开发具有新作用机制的选择性抑制剂提供了新的支架。(C)2014爱思唯尔有限公司版权所有。
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.