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

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出现的脑部病变由“错误折叠”蛋白质的原纤维组成。因此，最近的许多研究都集中在分子伴侣上，分子伴侣是负责维持蛋白质折叠或介导不可修复的蛋白质降解的细胞机制。在分子伴侣中，热休克蛋白90（Hsp 90）已成为调节多分子伴侣复合物的主要枢纽，其允许细胞对应激和蛋白质变性的特异性反应。有证据表明，Hsp 90的抑制剂激活特定的伴侣复合物，即Hsp 90，Hsp 70和CHIP。在AD神经病理学的转基因小鼠模型中，这些分子伴侣复合物的激活或上调减少了淀粉样肽（Ap）聚集体和纤维状Tau蛋白。然而，大多数已知的Hsp 90抑制剂是相当有毒的。我们已经确定了两种新的Hsp 90靶向药物，它们可以显着保护培养中的原代神经元免受A肽引起的毒性，并减少异常的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。拟议研究计划的总体目标是通过综合、迭代和合理的药物发现计划，确定GLP和GMP第一非人道使能研究的开发候选药物。新型Hsp 90抑制剂的临床前概念验证将通过表征最有希望的化学先导候选物在AD的三重转基因（3xTg-AD）小鼠模型中的体内作用来确定，所述AD随着年龄的增加而在脑中发展记忆缺陷和A？斑块和NFT样Tau聚集体。该计划的具体目标是：（1）合成克量的有前途的化学先导候选物，第一个被指定为“KU 32”和“A4”，以允许这些试剂的体内概念验证和药物安全性的全面表征。(2)为了测试有希望的化学先导候选物（前两种是KU 32和A4）在逆转或“治疗”通常存在于老年3xTg-AD小鼠脑中的认知障碍和神经病理学病变方面的体内功效。(3)为了测试长期施用有希望的化学先导候选物（前两种是KU 32和A4）在预防或延迟3xTg-AD小鼠模型中认知障碍的出现方面的体内功效。(4)确定具有改善的疗效、药物安全性和“可药用性”特性的开发候选药物。识别具有这些特性的候选药物将为提交研究性新药申请奠定基础。靶向Hsp 90蛋白复合物用于AD和以聚集蛋白质的积累为特征的其他神经退行性疾病的治疗干预有很强的实验基础。该项目的成功完成将推动这一概念走向临床开发。

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.