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'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics

“新型 Shc 阻滞剂作为潜在的阿尔茨海默病治疗药物

基本信息

批准号：
10395302
负责人：
Gino A Cortopassi
金额：
$ 30.47万
依托单位：
BUTO CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395302
关键词：
3-Dimensional Address Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic American Amyloid beta-Protein Animal Disease Models Animals Anti-Inflammatory Agents Binding Biological Biological Assay Blood Brain Brain-Derived Neurotrophic Factor Cells Chemicals Clinical Pharmacology Cognitive deficits Defect Dementia Development Plans Diet Disease Progression Dose Drug Kinetics Genetic Growth Factor Hippocampus (Brain)Human IRS1 gene Inflammation Inflammatory Insulin Insulin Receptor Laboratories Lead Maximum Tolerated Dose Measurement Memory Metabolic Methods Mus Nerve Degeneration Neurofibrillary Tangles Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Oxidative Stress PIK3CG gene PTEN gene Pathway interactions Penetrance Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phosphorylation Phosphotyrosine Proteins Resistance Safety Signal Transduction Symptoms Synapses Testing Text Therapeutic Therapeutic Index TimeLine Toxic effect Tyrosine age related apolipoprotein E-4 blood-brain barrier penetration cerebrovascular cognitive function conditioned fear drug development efficacy study experimental study in silico in vivo inhibitor/antagonist insulin sensitizing drugs knock-down mouse model neurobehavioral neuroprotection new therapeutic target novel object recognition pre-clinical resilience response scaffold screening small molecule targeted treatment three-dimensional modeling

项目摘要

Abstract. Alzheimer’s disease (AD) affects more than 5M Americans today, and is the most common cause of dementia in adults. While current medications slightly delay symptoms, no medications exist to cure or stop disease progression. A current focus at NIA is to identify novel drug targets, that address resilience to AD; also, there is an increasing perspective at NIA that Multi-target therapy may be necessary to overcome AD. We present the novel drug target Shc, which was recently shown to be a major resilience factor in conversion from human MCI to AD1, and whose activity rises in AD hippocampus2. Also, PSAPP mice with genetically decreased Shc protein had increased cognitive function and memory and survival, with the same burden of plaques and tangles-- thus Shc reduction represents a novel target whose reduction enables a neuroprotective 'resilience' mechanism3. Mice with genetic Shc deficiency are also protected from age related cerebrovascular dysfunction4 ALS5 and MS6, so reduction of Shc activity increases neuroprotection and resilience in multiple neurodegenerative conditions. To try to mimic the demonstrated neuroprotective benefit of genetic Shc reduction with a small molecule, we started with a repurposing approach to isolate 6 chemical scaffolds with Shc blocking activity7. Then a novel 3- dimensional scaffold search was carried out to identify 400 new molecules on completely novel scaffolds. These 400 have been winnowed down to a flock of 40 molecules through screening paradigms described in the application and tested them in 20 HTS assays to confer neural cell resistance to amyloid beta and picked the 5 most neuroprotective. PK experiments on the 2 most neuro-protective revealed a better brain penetrance of one molecule. Thus Buto's Aims are (1) to identify the Maximum Tolerated Dose (MTD) of this molecule, 2) to determine Brain and Blood PBMC target engagement in a mouse model of oxidative stress, and 3) to determine efficacy in the 5XFAD and ApoE4 mouse model. These Aims, once achieved, will determine the extent to which molecules that hit a completely novel and never-drugged AD target Shc, are acceptable pre-clinical pharmacological candidates, and set the stage for further partnering of Shc inhibitors in this indication.

摘要。阿尔茨海默病（AD）今天影响着超过500万美国人，是最常见的原因