AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans
AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans
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DOI：
10.1111/jnc.12203
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发表时间：
2013-05-01
影响因子：
4.7
通讯作者：
Bhat, Ratan V.
中科院分区：
文献类型：
--
作者：
Georgievska, Biljana;Sandin, Johan;Bhat, Ratan V.
导致tau从微管脱离和聚集的异常tau磷酸化是阿尔茨海默病中观察到的神经元功能障碍、变性和神经病理学中的关键事件。糖原合成酶激酶-3（GSK 3）是用于治疗阿尔茨海默病和相关tau蛋白病的药物发现的关键靶标，因为其可能使蛋白质异常磷酸化并促成突触变性。我们报告了AZD 1080的发现，AZD 1080是一种有效的选择性GSK 3抑制剂，在1期临床研究中证明了外周靶点参与。AZD 1080抑制表达人tau蛋白的细胞和完整大鼠脑中的tau蛋白磷酸化。有趣的是，亚慢性但非急性给药AZD 1080可逆转MK-801诱导的缺陷，通过海马切片和小鼠认知测试中的长时程增强进行测量，表明功能障碍系统中突触可塑性缺陷的逆转需要GSK 3信号下游蛋白的长期修饰。对tau磷酸化的抑制模式揭示了延长的药效学效应，预测在人体中的给药频率较低。与临床前数据一致，在健康志愿者中进行的多次剂量递增研究中，在血液单核细胞中观察到糖原合酶活性的长期抑制，这提供了人类外周靶点与选择性GSK 3抑制剂结合的证据。
Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase-3 (GSK3) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies. AZD1080 inhibits tau phosphorylation in cells expressing human tau and in intact rat brain. Interestingly, subchronic but not acute administration with AZD1080 reverses MK-801-induced deficits, measured by long-term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3 signaling. The inhibitory pattern on tau phosphorylation reveals a prolonged pharmacodynamic effect predicting less frequent dosing in humans. Consistent with the preclinical data, in multiple ascending dose studies in healthy volunteers, a prolonged suppression of glycogen synthase activity was observed in blood mononuclear cells providing evidence of peripheral target engagement with a selective GSK3 inhibitor in humans.