STEP inhibitors for intervention in Alzheimer's Disease

STEP 抑制剂干预阿尔茨海默病

• 批准号: 8208923
• 负责人: Lutz Tautz
• 金额: $ 4.78万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208923
• 关键词: AMPA Receptors; Ablation; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Antibodies; Attenuated; Autoimmune Diseases; Biological Assay; Brain; Cell membrane; Cells; Chemicals; Cognitive; Collaborations; Complex; Corpus striatum structure; Data; Development; Diabetes Mellitus; Disease; Enzymes; Equilibrium; Extracellular Domain; Failure; Functional disorder; Generations; GluR2 subunit AMPA receptor; Glutamate Receptor; Goals; Hand; Health; Hippocampus (Brain); Human; Injection of therapeutic agent; Intervention; Knockout Mice; Lead; Letters; Libraries; Malignant Neoplasms; Mediating; Membrane; Memory; Modeling; Mus; N-Methyl-D-Aspartate Receptors; NR1 gene; Neurodegenerative Disorders; Neurons; Patients; Phase III Clinical Trials; Phosphoric Monoester Hydrolases; Phosphorylation; Prefrontal Cortex; Process; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Proteins; Rattus; Regulation; Running; Screening procedure; Slice; Structure; Surface; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Tyrosine Phosphorylation; Western Blotting; Work; base; cognitive function; counterscreen; cytotoxicity; gamma secretase; genetic manipulation; high throughput screening; human disease; immunocytochemistry; improved; in vitro Assay; in vivo; inhibitor/antagonist; milligram; mouse model; multicatalytic endopeptidase complex; phosphatase inhibitor; small molecule; small molecule libraries; synaptic function; trafficking

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.

描述(申请人提供)：蛋白质酪氨酸磷酸化和去磷酸化之间的动态平衡失调对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。这是酪氨酸磷酸酶抑制剂首次被提出用于改善阿尔茨海默病(AD)的认知功能。纹状体富含磷酸酶(STEP)是一种脑特异性蛋白酪氨酸磷酸酶，在记忆巩固发生的区域高表达，并调节NMDAR的内化。我们最近的工作表明，在人类AD患者和AD动物模型的前额叶皮质中，STEP水平升高。此外，在一个三重转基因AD小鼠模型中，使用遗传操作来减少STEP活性，我们发现STEP水平的降低可以减轻6个月大的3xTg-AD小鼠观察到的认知和细胞缺陷。步骤抑制剂可能被证明对阿尔茨海默病的治疗是一种假设，这是当前降低Abeta水平的范例向抑制Abeta下游靶点的转变。伽马分泌酶抑制剂Semagacestat最近在III期临床试验中失败，表明显然需要其他方法。这项提议寻求产生第一步特异的抑制剂。除了可用于筛查的HTS分析外，我们还拥有二次分析、轮廓分析以及基于细胞和体内的分析，以验证、表征HITS并确定其优先顺序。我们手头有毫克量的高纯度STEP，因此STEP抑制剂的HTS可以立即开始。