Development of STEP Allosteric Inhibitors as Novel Therapeutics for Alzheimer's Disease

STEP 变构抑制剂的开发作为阿尔茨海默病的新疗法

基本信息

批准号：
10053075
负责人：
Lutz Tautz
金额：
$ 95.83万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053075
关键词：
3xTg-AD mouse AMPA Receptors Acids Active Sites Adverse effects Allosteric Site Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapeutic Attenuated Back Behavioral Binding Biochemical Biological Assay Blood - brain barrier anatomy Catalytic Domain Cell Line Cell model Cells Characteristics Chemicals Chemistry Chronic Cognitive Cognitive deficits Collaborations Computer Models Corpus striatum structure DNA Data Development Disease Drug Targeting Early treatment Endocytosis Ensure Excretory function Face Family member Fragile X Syndrome Functional disorder Genetic Glutamate Receptor Glutamates Goals Human Impaired cognition Institutes Knock-out Knockout Mice Label Length Link Metabolism Mitogen-Activated Protein Kinases Modeling Mus N-Methyl-D-Aspartate Receptors NR2B NMDA receptor Neurodegenerative Disorders Neurons Organism Parkinson Disease Pharmaceutical Preparations Pharmacology Phospho-Specific Antibodies Phosphoric Monoester Hydrolases Phosphotransferases Property Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Proto-Oncogene Proteins c-fyn Reporting Safety Schizophrenia Series Signal Transduction Specificity Structure-Activity Relationship Sulfhydryl Compounds Surface Synapses Technology Testing Toxic effect X-Ray Crystallography absorption base design drug discovery efficacy testing experience high throughput screening improved in vivo induced pluripotent stem cell inhibitor/antagonist innovation lead series mouse model neuropsychiatric disorder new therapeutic target novel novel therapeutics p38 Mitogen Activated Protein Kinase phosphatase inhibitor postsynaptic receptor scaffold screening small molecule success synaptic function targeted treatment treatment strategy

项目摘要

PROJECT SUMMARY STriatal-Enriched Tyrosine Phosphatase (STEP) is a neuron-specific protein tyrosine phosphatase (PTP) and a novel therapeutic target for Alzheimer's disease (AD), a debilitating neurodegenerative disorder for which currently no cure exists. Recent studies indicate that STEP is overactive in AD and other neurodegenerative and neuropsychiatric disorders. The emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits in these diseases. Knockout or pharmacological inhibition of STEP in a mouse model of AD decreases the biochemical and cognitive deficits in these mice, validating STEP as a novel drug target for the treatment of AD. However, the only reported STEP inhibitor with cellular and in vivo activity is a benzopentathiepin (TC-2153) that is known to modify DNA, thus likely causing adverse effects when given chronically. In this proposal we plan to develop the first selective and drug-like inhibitors of STEP for proof-of-concept (POC) studies in AD mouse models. Previous efforts to generate more drug-like STEP inhibitors have failed. These prior high-throughput screening (HTS) efforts utilized simple biochemical screening assays with truncated STEP constructs that only contained the catalytic domain. Thus, they favored the identification of compounds that target the highly conserved active site and are not selective for STEP. We have developed a robust HTS platform based on protein thermal shift (PTS) technology that can detect small molecule binding to full-length STEP in 384-well format. A sequence of secondary assays to further characterize hits is in place, as well as crucial collaborations, ensuring the greatest likelihood of success in the search for small molecules that are suitable for POC studies aimed at establishing a STEP-based treatment strategy in AD. In Aim 1 we will perform HTS for STEP allosteric inhibitors using our PTS- based screening platform. We will confirm and characterize hit compounds and select the most promising scaffolds for chemical optimization in Aim 2, where we will improve STEP inhibitor potency, selectivity, and drug- like properties. In Aim 3, we will evaluate selected inhibitors in cellular models for efficacy and specificity. Our overall goal is to develop at least one lead series and one back-up series of potent and specific STEP inhibitor probes that are ready for subsequent testing and optimization for in vivo studies.

项目摘要富含纹状体的酪氨酸磷酸酶（Step）是神经元特异性蛋白酪氨酸磷酸酶（PTP）和A 阿尔茨海默氏病（AD）的新型治疗靶标，这是一种使人衰弱的神经退行性疾病目前尚无治愈。最近的研究表明，AD和其他神经退行性的步骤过度活跃，并且神经精神疾病。紧急模型表明，步骤活动的增加会干扰突触功能并有助于这些疾病中的特征认知和行为缺陷。在小鼠AD模型中对步骤的敲除或药理抑制可降低生化和这些小鼠的认知缺陷，将步骤验证为AD治疗的新型药物靶标。但是，仅报道了具有细胞和体内活性的步骤抑制剂是苯并富汀（TC-2153），已知是已知的修改DNA，因此在长期给予时可能会导致不良反应。在此提案中，我们计划开发在AD小鼠模型中，用于概念验证（POC）研究的第一个选择性和类似药物样的抑制剂。以前的产生更多类似药物的步骤抑制剂的努力失败了。这些先前的高通量筛选（HTS）努力利用了简单的生化筛查测定法，截短的步骤结构仅包含催化域。因此，他们赞成鉴定针对高度保守活性位点的化合物并且不是步骤的选择性。我们开发了一个基于蛋白质热移（PTS）的强大HTS平台可以以384孔格式检测到与全长步骤结合的小分子的技术。一个序列进一步表征热门的次要测定以及关键的合作，确保最大的在寻找适合POC研究的小分子中成功的可能性，旨在建立一个基于步骤的治疗策略。在AIM 1中，我们将使用我们的PTS-执行用于步骤变构抑制剂的HTS- 基于筛选平台。我们将确认并表征命中化合物，并选择最有前途的在AIM 2中进行化学优化的脚手架，我们将提高步骤抑制剂效力，选择性和药物 - 喜欢属性。在AIM 3中，我们将评估细胞模型中选定的抑制剂的功效和特异性。我们的总体目标是开发至少一个铅系列和一个备用系列有效和特定的步骤抑制剂准备进行体内研究的探针进行后续测试和优化。