A novel DYRK1A (Dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro
A novel DYRK1A (Dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro
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DOI：
10.1111/jnc.13018
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发表时间：
2015-05-01
影响因子：
4.7
通讯作者：
Desire, Laurent
中科院分区：
文献类型：
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作者：
Coutadeur, Severine;Benyamine, Helene;Desire, Laurent
双特异性酪氨酸磷酸化调节激酶1A（DYRK 1A）基因位于21号染色体上的唐氏综合征（DS）关键区域内，并且涉及与在DS中观察到的早发性阿尔茨海默病（AD）相关的Tau和淀粉样蛋白病理的产生。DYRK 1A还被发现与散发性AD中的神经元缠结相关，并使关键的AD参与者（Tau、淀粉样前体、蛋白质等）磷酸化。因此，DYRK 1A可能是改变Tau和淀粉样蛋白β（A）病理过程的重要治疗靶标。在这里，我们描述了EHT 5372（9-（2，4-二氯苯基氨基）噻唑并[5，4-f]喹唑啉-2-亚氨基甲酯），一种新型、高效（IC 50 =0.22 nM）的DYRK 1A抑制剂，对339种激酶具有高度选择性。使用其中通过siRNA抑制DYRK 1A减少和DYRK 1A过表达诱导Tau磷酸化或A产生的模型。在生化和细胞试验中，EHT 5372在多个AD相关位点抑制DYRK 1A诱导的Tau磷酸化。EHT 5372还使A诱导的Tau磷酸化和DYRK 1A刺激的A产生正常化。因此，DYRK 1A是A介导的Tau过度磷酸化的关键元件，其将Tau和淀粉样蛋白病理学联系起来。EHT 5372和其他同类化合物作为AD和其他Tau病的新型高潜力疗法值得进行体内研究。
The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (A) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50=0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or A production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both A-induced Tau phosphorylation and DYRK1A-stimulated A production. DYRK1A is thus as a key element of A-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies.