'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.

抽象的。阿尔茨海默氏病（AD）今天影响了500万以上的美国人，是最常见的原因成人的痴呆症。虽然目前的药物略有延迟症状，但没有药物可以治愈或停止疾病进展。 NIA目前的重点是确定新的药物靶标，该靶标能够解决AD的弹性。还， NIA的观点越来越多，即需要多目标疗法才能克服AD。我们在场新型药物靶SHC最近被证明是人类转化的主要弹性因素 MCI至AD1，其活性在AD Hippocampus2中升高。另外，PSAPP小鼠具有一般改进的SHC 蛋白质具有增加的认知功能，记忆和存活，并具有相同的斑块和缠结燃烧 - 因此，SHC还原代表了一个新的目标，其还原可实现神经保护性的“弹性”机制3。具有遗传性SHC缺乏症的小鼠也受到与年龄相关的脑血管功能障碍4 ALS5和MS6的保护因此，在多种神经退行性条件下，SHC活性的降低会增加神经保护和弹性。到尝试模仿遗传SHC减少的神经保护益处，我们开始通过重新利用方法，可以将6个化学支架与SHC阻断活性分离7。然后是小说3- 进行了尺寸脚手架搜索，以识别完全新颖的脚手架上的400个新分子。这些通过筛选范式所述应用并在20 hts测定中对它们进行了对淀粉样蛋白β的会议神经细胞耐药性的测试，并选择了5 大多数神经保护作用。对2个最神经保护的PK实验显示了一个更好的大脑渗透率分子。 Buto的目的是（1）确定该分子的最大耐受剂量（MTD），2）在氧化应激的小鼠模型中确定大脑和血液PBMC目标参与，3）确定 5xFAD和APOE4鼠标模型的效率。这些目标一旦实现，将确定击中完全新颖且永不毒的AD目标SHC的分子是可接受的临床前药理学候选物，并为在此指示中进一步合作SHC抑制剂奠定了基础。