STEP inhibitors for intervention in Alzheimer's Disease

描述（由申请人提供）：蛋白酪氨酸磷酸化和去磷酸化之间的动态平衡的紊乱对于许多严重疾病的发展至关重要，包括癌症、糖尿病和自身免疫性疾病。这是第一次提出酪氨酸磷酸酶抑制剂来改善阿尔茨海默病（AD）的认知功能。STriatal-Enriched Phosphatase（STEP）是一种脑特异性蛋白酪氨酸磷酸酶，其在记忆巩固发生的区域中高度表达，并调节NMDAR的内化。我们最近的工作表明，STEP在人类AD患者和AD动物模型的前额叶皮层中升高。此外，使用遗传操作来降低三重转基因AD小鼠模型中的STEP活性，我们表明STEP水平的降低减弱了在6个月大的3xTg-AD小鼠中观察到的认知和细胞缺陷。STEP抑制剂可能被证明具有治疗AD的治疗性的假设是降低Abeta水平到抑制Abeta下游靶标的当前范例的转变。最近γ-分泌酶抑制剂semagacestat在III期临床试验中的失败表明，显然需要其他方法。该提案旨在产生第一个STEP特异性抑制剂。除了筛选就绪的HTS测定外，我们还具有二次测定、分析测定以及基于细胞的体内测定，以验证、表征和优先化命中。我们手头有毫克量的高纯STEP，因此STEP抑制剂的HTS可以立即开始。

DESCRIPTION (provided by applicant): Disturbance of the dynamic balance between protein tyrosine phosphorylation and dephosphorylation is crucial for the development of many serious conditions, including cancer, diabetes, and autoimmune disorders. This is the first time that tyrosine phosphatase inhibitors are being proposed to improve cognitive function in Alzheimer's disease (AD). STriatal-Enriched Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that is highly expressed in regions where consolidation of memory occurs and regulates the internalization of NMDARs. Our recent work demonstrates that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Moreover, using genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model, we showed that a decrease in STEP levels attenuates the cognitive and cellular deficits observed in six-month old 3xTg-AD mice. The hypothesis that STEP inhibitors may prove therapeutic for the treatment of AD is a shift in the current paradigm of reducing Abeta levels to inhibiting a downstream target of Abeta. The recent failure of the gamma-secretase inhibitor semagacestat in phase III clinical trials suggests that other approaches are clearly needed. This proposal seeks to generate the first STEP-specific inhibitors. Besides a screening ready HTS assay, we also have a secondary assay, profiling assays, as well as cell-based and in vivo assays in place to verify, characterize, and prioritize hits. We have milligram amounts of highly pure STEP in hand, so that HTS for STEP inhibitors could commence immediately.