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：
10260540
负责人：
Lutz Tautz
金额：
$ 90.25万
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/10260540
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.

项目概要 STriatal 富含酪氨酸磷酸酶 (STEP) 是一种神经元特异性蛋白酪氨酸磷酸酶 (PTP) 和阿尔茨海默病 (AD) 的新治疗靶点，这是一种使人衰弱的神经退行性疾病，目前尚无治愈方法。最近的研究表明，STEP 在 AD 和其他神经退行性疾病和其他疾病中过度活跃神经精神疾病。新兴模型表明，STEP 活动的增加会干扰突触功能并导致这些疾病的特征性认知和行为缺陷。在 AD 小鼠模型中敲除或药物抑制 STEP 会降低生化和这些小鼠的认知缺陷，验证了 STEP 作为治疗 AD 的新药物靶点。然而，唯一报道的具有细胞和体内活性的 STEP 抑制剂是苯并五硫平 (TC-2153)，已知它可以改变 DNA，因此长期服用可能会造成不良影响。在本提案中，我们计划开发第一个选择性的 STEP 类药物抑制剂，用于 AD 小鼠模型的概念验证 (POC) 研究。以前的生产更多类似药物的 STEP 抑制剂的努力失败了。这些先前的高通量筛选（HTS）研究人员利用简单的生化筛选测定法，使用截短的 STEP 构建体，仅包含催化域。因此，他们倾向于鉴定针对高度保守的活性位点的化合物并且对STEP没有选择性。我们开发了基于蛋白质热位移 (PTS) 的强大 HTS 平台该技术可以检测与 384 孔格式的全长 STEP 结合的小分子。一系列进一步表征命中的二次测定以及关键的合作都已到位，以确保最大程度的实现寻找适合 POC 研究的小分子的成功可能性，旨在建立 AD 中基于 STEP 的治疗策略。在目标 1 中，我们将使用我们的 PTS-对 STEP 变构抑制剂进行 HTS 基于筛选平台。我们将确认和表征热门化合物并选择最有希望的目标 2 中的化学优化支架，我们将提高 STEP 抑制剂的效力、选择性和药物- 喜欢属性。在目标 3 中，我们将在细胞模型中评估所选抑制剂的功效和特异性。我们的总体目标是开发至少一个先导系列和一个备用系列的有效且特异性的 STEP 抑制剂为体内研究的后续测试和优化做好准备的探针。