Novel Hsp90 Inhibitors to Reduce Misfolded Proteins in Alzheimer's Disease

新型 Hsp90 抑制剂可减少阿尔茨海默病中的错误折叠蛋白

基本信息

批准号：
7351215
负责人：
MARY L. MICHAELIS
金额：
$ 52.31万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7351215
关键词：
Age Age of Onset Alzheimer&apos s Disease Apoptosis Appearance Back Biochemical Blood - brain barrier anatomy Brain Cell Cycle Cells Chemical Structure Chemicals Chronic Clinical Cognitive Complex Contracts Data Development Dose Drug Kinetics Evaluation Foundations Geldanamycin Genes Goals Grant Guanosine Monophosphate HSP 90 inhibition Heat shock proteins Heat-Shock Proteins 90 Human Huntington Disease Impaired cognition In Vitro Investigational New Drug Application Kansas Lead Lesion Life Mediating Memory impairment Mitotic Molecular Chaperones Mus Mutation N-terminal Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinson Disease Peptides Performance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacy (field)Process Program Development Proliferating Property Protein Denaturation Proteins Protocols documentation Rattus Regulation Research Research Personnel Running Safety Senile Plaques Series Solubility Specificity Standards of Weights and Measures Stress Structure Tauopathies Testing Therapeutic Intervention Toxic effect Toxicology Transcriptional Activation Transgenic Organisms Universities Up-Regulation age related amyloid peptide analog base behavior test cell type chemical synthesis concept drug discovery drug efficacy feeding hyperphosphorylated tau improved in vivo inhibitor/antagonist interest mouse model neuronal survival neuropathology normal aging novel novel therapeutics performance tests pre-clinical prevent programs protein aggregate protein folding protein misfolding response scaffold stress protein tau Proteins tau aggregation tau mutation

项目摘要

DESCRIPTION (provided by applicant): Brain lesions that develop in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's are composed of fibrils of 'misfolded' proteins. Consequently much recent research has been focused on molecular chaperones, the cellular machinery responsible for maintaining protein folding or mediating the degradation of irreparably damaged proteins. Of the molecular chaperones, heat shock protein 90 (Hsp90) has emerged as a major hub for regulation of multi-chaperone complexes that allows for cell specific responses to stresses and protein denaturation. Evidence suggests that inhibitors of Hsp90 activate specific chaperone complexes, namely Hsp90, Hsp70, and CHIP. Activation or up-regulation of these chaperone complexes reduces amyloid peptide (Ap) aggregates and fibrillar Tau protein in transgenic mouse models of AD neuropathology. However, most known Hsp90 inhibitors are quite toxic. We have identified two new Hsp90-targeted agents that markedly protect primary neurons in culture against toxicity elicited by A¿ peptides and reduce abnormal Tau, but they do not produce any toxicity on their own. The compounds are protective for neurons at low nanomolar concentrations and appear to cross the blood brain barrier. The overall goal of the proposed research program is to identify, through an integrated, iterative, and rational drug discovery program, development candidates for GLP and GMP first-inhuman enabling studies. Preclinical proof-of-concept for novel Hsp90 inhibitors will be determined by characterizing the in vivo effects of the most promising chemical lead candidates in the triple transgenic (3xTg-AD) mouse model for AD that develops memory deficits and both A¿ plaques and NFT-like Tau aggregates in the brain with increasing age. The specific aims of the program are: (1) To synthesize gram quantities of promising chemical lead candidates, the first being designated as 'KU32' and 'A4, to permit full characterization of the in vivo proof-of-concept and drug safety properties of these agents. (2) To test the in vivo efficacy of promising chemical lead candidates, the first two being KU32 and A4, in reversing or 'treating' the cognitive impairment and neuropathological lesions normally present in the brains of older 3xTg-AD mice. (3) To test the in vivo efficacy of chronic administration of promising chemical lead candidates, the first two being KU32 and A4, in preventing or delaying the appearance of cognitive impairments in the 3xTg-AD mouse model. (4) To identify development candidates that possess improved efficacy, drug safety and 'druggability' properties. Identification of a candidate or candidates with these properties will lay the foundation for submission of an Investigational New Drug Application. There is a strong experimental basis for targeting Hsp90 protein complexes for therapeutic interventions in AD and other neurodegenerative diseases characterized by accumulations of aggregated proteins. Successful completion of this program will advance this concept toward clinical development.

描述（由申请人提供）：阿尔茨海默氏症（AD）和帕金森氏症等神经退行性疾病中发生的脑损伤是由“错误折叠”蛋白质的纤维组成的，最近的研究主要集中在分子伴侣上，即负责维持蛋白质的细胞机制。在分子伴侣中，热休克蛋白 90 (Hsp90) 已成为多伴侣调节的主要枢纽。有证据表明，Hsp90 的抑制剂可激活特定的伴侣复合物，即 Hsp90、Hsp70 和 CHIP，从而激活或上调这些伴侣复合物淀粉样肽 (Ap) 聚集体和纤维状 Tau。然而，大多数已知的 Hsp90 抑制剂具有相当大的毒性。 Hsp90 靶向药物可显着保护培养中的原代神经元免受 A¿ 引起的毒性肽并减少异常 Tau，但它们本身不会产生任何毒性，这些化合物在低纳摩尔浓度下对神经元具有保护作用，并且似乎可以穿过血脑屏障。综合、迭代和合理的药物发现计划，GLP 和 GMP 首次人体研究的候选药物开发将通过表征最有前途的化学先导候选药物的体内效应来确定新型 Hsp90 抑制剂的临床前概念验证。在 AD 的三重转基因 (3xTg-AD) 小鼠模型中，该模型出现记忆缺陷，并且 A¿随着年龄的增长，大脑中的斑块和类似 NFT 的 Tau 蛋白聚集体的具体目标是：（1）合成克数量的有前途的化学先导候选物，第一个被指定为“KU32”和“A4”，以允许完全合成。 (2) 测试有前途的化学先导候选物（前两个是 KU32 和 A4）在逆转或“治疗”认知障碍方面的体内功效和神经病理学病变通常存在于老年 3xTg-AD 小鼠的大脑中 (3) 测试长期施用有前途的化学先导候选物（前两种是 KU32 和 A4）在预防或延缓认知障碍出现方面的体内功效。 (4) 确定具有改善的功效、药物安全性和“成药性”特性的候选药物。确定具有这些特性的候选药物将为提交申请奠定基础。研究性新药应用针对 Hsp90 蛋白复合物治疗 AD 和其他以聚集蛋白积累为特征的神经退行性疾病有强有力的实验基础。该计划的成功完成将推动这一概念走向临床开发。