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A Novel Insulin Pathway Agonist for Alzheimer's Disease

一种治疗阿尔茨海默病的新型胰岛素途径激动剂

基本信息

批准号：
8520608
负责人：
HENRY W QUERFURTH
金额：
$ 14.77万
依托单位：
MEDCHEM PARTNERS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8520608
关键词：
Acids Acute Address Adverse effects Affect Agonist Alzheimer&apos s Disease Amyloid Animal Feed Apoptosis Binding Binding Sites Biochemical Biological Assay Brain Cell model Cell-Free System Cells Clinical Trials Consensus Coupled Cultured Cells Data Defect Deposition Detection Diabetes Mellitus Disease Progression Energy Metabolism Equilibrium Etiology Excision Focus Groups Future Glucose Goals Hippocampus (Brain)In Vitro Individual Insulin Insulin Resistance Insulin-Like Growth Factor I Insulinase Label Lead Libraries Life Literature Long-Term Potentiation Memory Metabolic Neurobiology Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Nutrient Outcome Output PDPK1 gene Pathogenesis Pathway interactions Peptides Permeability Pharmaceutical Preparations Phase Phase III Clinical Trials Phosphotransferases Property Protein Dephosphorylation Recombinants Risk Factors Schizophrenia Senile Plaques Side Signal Pathway Signal Transduction Site Slice Solid Specific qualifier value Structure Structure-Activity Relationship Synapses Synaptic plasticity System Testing Therapeutic Therapeutic Effect Toxic effect Transgenic Mice amyloid peptide analog base design drug discovery effective therapy environmental stressor high throughput screening human FRAP1 protein in vivo insulin sensitivity insulin signaling mTOR protein morris water maze mutant neuronal survival novel peptide A pre-clinical pro-apoptotic protein protein protein interaction public health relevance receptor scaffold sensor tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Even though the association of ¿-amyloid peptide (A¿) deposition and Alzheimer's Disease (AD) underpins the major hypothesis for disease progression and possibly causation and several drugs addressing the formation or removal of ¿-amyloid plaques have entered clinical trials, no effective therapy exists to date for AD. This reality calls for new targets that are not based on ¿-amyloid supply side or removal but address its toxic effects on critical neuronal survival, metabolic and plasticity pathways. There is widening recognition that AD is an insulin resistant state affecting the brain, a so-called 'type II diabetes' In our studies, we have found a potential novel therapy to both restore insulin sensitivity and hasten A¿ removal. We found literature precedence for an unnamed allosteric activator of the kinase PDK-1 (CAS 1180676-32-7 or PS48), a chlorophenyl pentenoic acid. When tested in cultured cells and cell-free systems, PS48 was found to be reverse the negative amyloid effect by restoring Akt activation. We propose to use its structure and activity as a scaffold for the discovery of additional like-acting compounds. In this way several small libraries based on PS48 will be prepared and tested to try and optimize the therapeutic effect and other pharmacologic properties of this lead compound.

描述(申请人提供)：尽管淀粉样蛋白(A)沉积与阿尔茨海默病(AD)之间的联系是疾病进展和可能原因的主要假说的基础，几种解决淀粉样斑块形成或移除的药物已经进入临床试验，但到目前为止还没有有效的治疗AD的方法。这一现实需要新的靶点，而不是基于淀粉样蛋白的供应面或移除，而是解决其对关键神经元存活、代谢和可塑性途径的毒性影响。人们越来越多地认识到，阿尔茨海默病是一种影响大脑的胰岛素抵抗状态，即所谓的“II型糖尿病”。在我们的研究中，我们发现了一种潜在的新疗法，既可以恢复胰岛素敏感性，又可以加速A？的清除。我们发现了一种未命名的变构激活剂，即一种氯苯基戊烯酸，它是一种未命名的变构激活剂，即pdk-1(CAS 1180676-32-7或PS48)。当在培养细胞和无细胞系统中进行测试时，发现PS48通过恢复Akt的激活来逆转负淀粉样蛋白效应。我们建议利用它的结构和活性作为发现更多类似作用化合物的支架。通过这种方式，有几个小图书馆将基于PS48进行制备和测试，以尝试和优化该先导化合物的治疗效果和其他药理性质。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration.

DOI：
10.1186/s13024-021-00428-5
发表时间：
2021-07-02
期刊：
Molecular neurodegeneration
影响因子：
15.1
作者：
Querfurth H;Lee HK
通讯作者：
Lee HK

A PDK-1 allosteric agonist improves spatial learning and memory in a βAPP/PS-1 transgenic mouse-high fat diet intervention model of Alzheimer's disease.

PDK-1 变构激动剂可改善阿尔茨海默病 βAPP/PS-1 转基因小鼠高脂肪饮食干预模型中的空间学习和记忆。

DOI：
10.1016/j.bbr.2022.114183
发表时间：
2023
期刊：
Behavioural brain research
影响因子：
2.7
作者：
Querfurth,Henry;Slitt,Angela;DiCamillo,Amy;Surles,Nathan;DeBoef,Brenton;Lee,Han-Kyu
通讯作者：
Lee,Han-Kyu