Indirubins inhibit glycogen synthase kinase-3β and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease -: A property common to most cycline-dependent kinase inhibitors?
Indirubins inhibit glycogen synthase kinase-3β and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease -: A property common to most cycline-dependent kinase inhibitors?
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DOI：
10.1074/jbc.m002466200
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发表时间：
2001-01-05
影响因子：
4.8
通讯作者：
Meijer, L
中科院分区：
文献类型：
--
作者：
Leclerc, S;Garnier, M;Meijer, L
双吲哚靛玉红是当归龙回丸的活性成分，当归龙回丸是一种用于治疗白血病等慢性疾病的传统中药配方。靛玉红的抗肿瘤特性似乎与其抗有丝分裂作用相关。靛玉红最近被描述为有效的（IC 50：50-100 nm）细胞周期蛋白依赖性激酶（CDK）的抑制剂，我们在这里报道靛玉红也是强效抑制剂（IC50：5-50 nM）的一种进化相关的激酶，糖原合成酶激酶-3 β（GSK-3 β），一系列吲哚和双吲哚对GSK-3 β、CDK 1/细胞周期蛋白B和CDK 5/p25的测试表明，只有靛玉红抑制这些激酶，构效关系研究还表明，靛玉红与GSK-3 β的ATP结合口袋的结合方式与它们与CDK的结合方式相似，其细节最近通过晶体学分析揭示。GSK-3 β，沿着CDK 5，是导致阿尔茨海默病中微管结合蛋白tau异常过度磷酸化的主要原因。靛玉红-3 '-单肟在体外和体内抑制阿尔茨海默病特异性位点的tau磷酸化因此，靛玉红在神经退行性疾病的研究和治疗中可能具有重要意义。靛玉红-3 '-单肟还通过Thr-75上的CDK 5抑制DARPP-32的体内磷酸化，从而模拟多巴胺在纹状体中的作用之一。最后，我们表明，许多但不是所有报道的CDK抑制剂都是GSK-3 β的强效抑制剂，在这种程度上，这些GSK-3 β作用：CDK抑制剂实际上有助于其抗有丝分裂和抗肿瘤特性仍有待确定。靛玉红类化合物构成了第一个要描述的GSK-3 β低纳摩尔抑制剂家族。
The bis-indole indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used in the treatment of chronic diseases such as leukemias. The antitumoral properties of indirubin appear to correlate with their antimitotic effects. Indirubins were recently described as potent (IC50: 50-100 nm) inhibitors of cyclin-dependent kinases (CDKs), We report here that indirubins are also powerful inhibitors (IC50: 5-50 nM) of an evolutionarily related kinase, glycogen synthase kinase-3 beta (GSK-3 beta), Testing of a series of indoles and bis-indoles against GSK-3 beta, CDK1/cyclin B, and CDK5/p25 shows that only indirubins inhibit these kinases, The structure-activity relationship study also suggests that indirubins bind to GSK-3 beta 's ATP binding pocket in a way similar to their binding to CDKs, the details of which were recently revealed by crystallographic analysis. GSK-3 beta, along with CDK5, is responsible for most of the abnormal hyperphosphorylation of the microtubule-binding protein tau observed in Alzheimer's disease. Indirubin-3'-monoxime inhibits tau phosphorylation in vitro and in vivo at Alzheimer's disease-specific sites. Indirubins may thus have important implications in the study and treatment of neurodegenerative disorders. Indirubin-3'-monoxime also inhibits the in vivo phosphorylation of DARPP-32 by CDK5 on Thr-75, thereby mimicking one of the effects of dopamine in the striatum, Finally, we show that many, but not all, reported CDK inhibitors are powerful inhibitors of GSK-3 beta, To which extent these GSK-3 beta effects of: CDK inhibitors actually contribute to their antimitotic and antitumoral properties remains to be determined. Indirubins constitute the first family of low nanomolar inhibitors of GSK-3 beta to be described.