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

描述（由申请人提供）：在阿尔茨海默氏症（AD）和帕金森病等神经退行性疾病中发生的脑损伤是由“错误折叠”的蛋白质原纤维组成的。因此，最近的许多研究都集中在分子伴侣上，这是一种负责维持蛋白质折叠或介导不可修复损伤蛋白质降解的细胞机制。在分子伴侣中，热休克蛋白90 （Hsp90）已成为调节多伴侣复合物的主要枢纽，该复合物允许细胞对应激和蛋白质变性做出特异性反应。有证据表明，Hsp90抑制剂可激活特异性伴侣复合物，即Hsp90、Hsp70和CHIP。在AD神经病理学转基因小鼠模型中，这些伴侣复合物的激活或上调可减少淀粉样肽（Ap）聚集和纤维状Tau蛋白。然而，大多数已知的Hsp90抑制剂毒性很大。我们已经确定了两种新的hsp90靶向药物，它们可以显著保护培养的原代神经元免受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一个集成的、迭代的、合理的药物发现计划，确定GLP和GMP的候选药物的第一次非人类研究。新型Hsp90抑制剂的临床前概念验证将通过在三重转基因（3xTg-AD） AD小鼠模型中表征最有希望的化学先导候选物的体内效应来确定，该模型随着年龄的增长在大脑中出现记忆缺陷和A¿斑块和nft样Tau聚集。该项目的具体目标是：(1)合成克数量的有前途的化学先导候选物，首先被指定为“KU32”和“A4”，以便对这些制剂的体内概念验证和药物安全性进行全面表征。(2)测试有希望的化学先导候选物的体内功效，前两种是KU32和A4，在逆转或“治疗”老年3xTg-AD小鼠大脑中通常存在的认知障碍和神经病理病变方面。(3)在3xTg-AD小鼠模型中，检测慢性给药有前景的候选化学先导物（前两种为KU32和A4）在体内预防或延缓认知障碍出现的效果。(4)确定具有更高疗效、药物安全性和“可药物性”特性的开发候选药物。确定具有这些特性的候选药物将为提交研究新药申请奠定基础。针对Hsp90蛋白复合物对阿尔茨海默病和其他以聚集蛋白积累为特征的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发展。

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.