Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription
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DOI：
10.1016/s1074-5521(00)00025-9
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发表时间：
2000-10-01
影响因子：
--
通讯作者：
Holder, JC
中科院分区：
文献类型：
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作者：
Coghlan, MP;Culbert, AA;Holder, JC
背景资料：糖原合成酶激酶-3（GSK-8）是一种丝氨酸/苏氨酸蛋白激酶，其活性被多种细胞外刺激物抑制，包括胰岛素、生长因子、细胞特化因子和细胞粘附。因此，已提出GSK-3活性的抑制在引起多效性细胞应答的众多信号传导途径的调节中发挥作用。结果：SB-216763和SB-415286是两种结构不同的马来酰亚胺类化合物，在体外以ATP竞争方式抑制GSK-3 α，K（j）分别为9 nM和31 nM。这些化合物以相似的效力抑制GSK-3 β。然而，这两种化合物都不能显著抑制一组24种其他蛋白激酶中的任何一种。此外，用任一化合物处理细胞刺激已知抑制GSK-3活性的细胞外刺激的特征性反应。因此，SB-216763和SB-415286刺激人肝细胞中的糖原合成，并诱导HEK 293细胞中β-连环蛋白-LEF/TCF调节的报告基因的表达。在这两种情况下，化合物治疗被证明抑制细胞GSK-8的活性评估激活糖原合成酶，这是一个直接的目标，这kinase.Conclusions：SB-216763和SB-415286是新的，有效的和选择性的细胞渗透抑制剂GSK-3。因此，这些化合物代表了有价值的药理学工具，可以进一步阐明GSK-3在细胞信号传导中的作用。此外，类似化合物的开发可用于治疗与GSK-3活性升高相关的疾病状态，如非胰岛素依赖性糖尿病和神经变性疾病。
Background: Glycogen synthase kinase-3 (GSK-8) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3 alpha in vitro, with K(j)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3 beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta -catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-8 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.