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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：
10410545
负责人：
Lutz Tautz
金额：
$ 85.15万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410545
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 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.

项目总结