Brain penetrant Hsp90 inhibitors for Alzheimer's disease

治疗阿尔茨海默病的脑渗透性 Hsp90 抑制剂

• 批准号: 8780832
• 负责人: MARCIE A GLICKSMAN
• 金额: $ 95.86万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780832
• 关键词: Address; Affect; Aftercare; Alzheimer' s Disease; Amygdaloid structure; Amyloid beta-Protein; Award; Back; Behavioral; Biochemical; Biological Assay; Biological Markers; Brain; Cerebrospinal Fluid; Clinical; Clinical Treatment; Cyclin-Dependent Kinases; Data; Deposition; Deterioration; Development; Disease; Disease Progression; Dose; Drug Formulations; Drug Kinetics; Funding; Generations; HSP 90 inhibition; Health; Heat Stress Disorders; Heat-Shock Proteins 90; Hippocampus (Brain); Human; In Vitro; Individual; Investigational New Drug Application; Lead; Learning; Measurement; Memory; Molecular Chaperones; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Property; Proteins; Publishing; Regimen; Reporting; Research; Research Support; Role; Running; Safety; Small Business Technology Transfer Research; Sodium; Solubility; Structure-Activity Relationship; Tauopathies; Therapeutic; Time; TimeLine; Tissues; Toxicology; Transgenic Mice; Validation; Variant; Work; abnormally phosphorylated tau; aged; anticancer research; behavior measurement; brain tissue; cancer therapy; drinking water; drug candidate; improved; in vivo; inhibitor/antagonist; manufacturing scale-up; mild cognitive impairment; morris water maze; mouse model; neuropathology; novel; novel strategies; phase 2 study; protein degradation; selenate; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; tau-1; therapy development; transgenic model of alzheimer disease; treatment effect; tumor growth

DESCRIPTION (provided by applicant): Neurodegeneration in Alzheimer's disease (AD) may result from deposition of Aβ 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 heat shock protein 90 (Hsp90) as a promising new approach to affect the disease progression of AD. This proposal builds on the specific aims set forth and achieved under the STTR Phase I funding - a) to conduct structure-activity relationship studies to obtain brain permeable Hsp90 inhibitors and b) to evaluate biochemical and cellular Hsp90 inhibition. These efforts yielded novel, proprietary Hsp90 inhibitors with acceptable drug-like properties including good brain concentration. Since the conclusion of Phase I funding, Yuma Therapeutics has generated pharmacokinetic data in mice for an early lead compound, YT-17, further supporting its drug-like properties. The proposed studies for Phase II focus on a) evaluating our lead compound in an in vivo transgenic mouse model of tauopathy on the levels of total tau and phosphorylated-tau in cerebrospinal fluid, tau neuropathology, and behavioral outcomes; b) manufacturing scale-up of active pharmaceutical ingredient (API) of a lead candidate and initiate in vivo toxicology studies; and c) formulation work on the API.

描述（由申请人提供）：阿尔茨海默病（AD）中的神经变性可能是由于 Aβ 在脑组织中以斑块形式沉积所致。然而，人们很少努力阐明含有 tau 蛋白的神经原纤维缠结 (NFT) 在 AD 中的作用。越来越多的证据表明，含有 NFT 的 tau 蛋白是 AD 和其他神经退行性疾病发生和进展的重要组成部分。在该提案中，tau 通路通过抑制分子伴侣热休克蛋白 90 (Hsp90) 为目标，作为影响 AD 疾病进展的一种有前途的新方法。该提案建立在 STTR 第一阶段资助下提出和实现的具体目标之上 - a）进行结构-活性关系研究以获得脑可渗透性 Hsp90 抑制剂，b）评估生化和细胞 Hsp90 抑制。这些努力产生了新型、专有的 Hsp90 抑制剂，具有可接受的药物样特性，包括良好的脑浓度。自第一阶段资金结束以来，Yuma Therapeutics 已经在小鼠中生成了早期先导化合物 YT-17 的药代动力学数据，进一步支持了其类似药物的特性。拟议的 II 期研究重点是 a) 在 tau 蛋白病体内转基因小鼠模型中评估我们的先导化合物对脑脊液中总 tau 蛋白和磷酸化 tau 蛋白的水平、tau 蛋白神经病理学和行为结果； b) 扩大主要候选药物活性药物成分（API）的生产规模并启动体内毒理学研究； c) API 的制定工作。