CSF Tau Biomarker-guided Development of Hsp90 Inhibitors for Alzheimer's Disease

CSF Tau 生物标志物引导开发治疗阿尔茨海默病的 Hsp90 抑制剂

• 批准号: 8311461
• 负责人: Gregory D Cuny
• 金额: $ 20.08万
• 依托单位: YUMA THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311461
• 关键词: Accounting; Affect; Affinity; Alzheimer' s Disease; Amyloid; Binding; Biochemical; Biological Assay; Biological Markers; Brain; Cell Death; Cell model; Cells; Cerebrospinal Fluid; Chromosomes, Human, Pair 17; Clinical; Clinical Trials; Cognition; Communication; Complex; Computer Simulation; Cyclin-Dependent Kinases; Dementia; Dependence; Deposition; Development; Disease; Disease Outcome; Disease Progression; Dissociation; Dose; Frontotemporal Dementia; Genes; Glycogen Synthase Kinase 3; Goals; Grant; HSP 90 inhibition; Heat-Shock Proteins 90; In Vitro; Inherited; Inhibitory Concentration 50; Link; Measures; Medical; Microtubules; Molecular Chaperones; Molecular Target; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Normal Cell; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Population Study; Proteins; Relative (related person); Research; Role; Senile Plaques; Severities; Solubility; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Agents; Tissues; abnormally phosphorylated tau; abstracting; addiction; base; brain tissue; chemical property; cytotoxicity; design; drug development; drug discovery; heat-shock factor 1; improved; in vivo; inhibitor/antagonist; mild neurocognitive impairment; neoplastic cell; neuroblastoma cell; neurofibrillary tangle formation; novel; novel strategies; oncology; physical model; scaffold; secretase; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; tau-1; tumor

DESCRIPTION (provided by applicant): Research & Related Other Project Information Item 7. Project Summary/Abstract Neurodegeneration in Alzheimer's disease (AD) may result from deposition of A¿ as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone Hsp90 as a promising new approach to affect the disease progression of AD. The goal of this grant is to optimize two structurally distinct scaffolds aided by in silico modeling and physical-chemical property predictions in order to generate novel brain permeable Hsp90 inhibitors as AD therapeutics. Subsequently, these compounds will be clinically developed for the treatment of AD using CSF biomarkers, as well as improved cognition, for in vivo efficacy determinations. PUBLIC HEALTH RELEVANCE: Research & Related Other Project Information Item 8. Project Narrative This research is focused on identifying potential drug candidates to treat Alzheimer's disease (AD) and in this way it addresses NIA's priorities to support research on health and disease in the aged. Furthermore, this project targets the tau pathway as a promising new approach to affect the disease progression of AD.

描述（由申请人提供）：研究及相关其他项目信息第 7 项。项目摘要/摘要阿尔茨海默病 (AD) 的神经变性可能是由 A¿ 的沉积引起的然而，人们很少努力阐明含有 tau 的神经原纤维缠结 (NFT) 在 AD 中的作用，越来越多的证据表明，含有 tau 的 NFT 是 AD 和其他神经退行性疾病的发生和进展的重要组成部分。在这项提案中，tau 通路的目标是通过抑制分子伴侣 Hsp90 作为影响 AD 疾病进展的一种有前途的新方法。在计算机建模和物理化学性质预测的帮助下，优化两种结构不同的支架，以产生新型的脑可渗透性 Hsp90 抑制剂作为 AD 治疗剂。随后，这些化合物将在临床上开发，用于使用 CSF 生物标志物治疗 AD，并改善认知，用于体内功效测定。 公共健康相关性：研究及相关其他项目信息项目 8. 项目叙述 本研究的重点是确定治疗阿尔茨海默病 (AD) 的潜在候选药物，并以此方式解决 NIA 支持老年人健康和疾病研究的优先事项。此外，该项目将 tau 通路作为影响 AD 疾病进展的一种有前途的新方法。