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：
7796649
负责人：
MARY L. MICHAELIS
金额：
$ 55.84万
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/7796649
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 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 Stress Structure Tauopathies Testing Therapeutic Intervention Toxic effect Toxicology Transgenic Mice Transgenic Organisms Universities Up-Regulation age related amyloid peptide analog base behavior test cell type chemical synthesis drug discovery drug efficacy feeding hyperphosphorylated tau improved in vivo inhibitor/antagonist interest mouse model neuronal survival neuropathology new therapeutic target normal aging novel performance tests pre-clinical prevent programs protein aggregate protein complex 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（由适用提供）：在阿尔茨海默氏症（AD）和帕金森氏症等神经退行性疾病中发展的脑损伤，由“错误折叠”蛋白质的原纤维组成。因此，最近的许多研究集中在分子伴侣上，分子伴侣是负责维持蛋白质折叠或介导无法损坏的蛋白质降解的细胞机制。在分子伴侣中，热休克蛋白90（HSP90）已成为调节多芯酮复合物的主要枢纽，该络合物允许对胁迫和蛋白质变性的细胞特异性响应。证据表明，HSP90的抑制剂激活了特定的链酮复合物，即HSP90，HSP70和CHIP。这些链酮复合物的激活或上调减少了AD神经病理的转基因小鼠模型中的淀粉样蛋白（AP）聚集体和原纤维Tau蛋白。但是，大多数已知的HSP90抑制剂具有很大的毒性。我们已经确定了两种新的HSP90靶向药物，它们在培养中明显保护原发性神经元免受A肽引起的毒性并减少异常TAU的毒性，但它们不会自行产生任何毒性。这些化合物在低纳摩尔浓度下受到神经元的保护，并且似乎越过了血脑屏障。拟议的研究计划的总体目标是通过一项综合，迭代和合理的药物发现计划，GLP和GMP的开发候选者和GMP首次企业促进研究来确定。新型HSP90抑制剂的临床前概念概念可以通过表征三重转基因（3XTG-AD）小鼠模型中最有前途的化学铅候选物的体内影响来确定，该模型的体内候选者的体内效应定义了记忆的定义，并且随着年龄的增长，a plaques和Nft-like like tau tau骨料均在大脑中。该程序的具体目的是：（1）合成革兰氏量的有前途的化学铅候选者，第一个被指定为“ KU32”和“ A4），以允许对这些药物的体内概念概念和药物安全性的全面表征。（2）测试有前途的化学铅候选物的体内效率，前两个是Ku32和A4，以反向或“治疗”通常存在于较老的3XTG-AD小鼠大脑中的认知障碍和神经病理病变。（3）测试承诺的化学铅候选者长期给药的体内效率，前两个是KU32和A4，以防止或延迟3xTG-AD小鼠模型中认知障碍的出现。（4）确定具有提高效率，药物安全性和“可药物性”特性的发展候选者。确定具有这些特性的候选人或候选人将为提交研究新药申请的基础。针对HSP90蛋白复合物的AD和其他神经退行性疾病的治疗干预措施的实验基础有很强的基础，其特征是聚集的蛋白质的积累。该计划的成功完成将把这一概念推向临床发展。