Brain penetrant Hsp90 inhibitors for Alzheimer's disease

描述（由申请人提供）：阿尔茨海默病（AD）的神经退行性变可能是由脑组织中Aβ斑块沉积引起的。然而，关于含tau的神经原纤维缠结（nft）在AD中的作用的研究较少。越来越多的证据表明，含有tau的nft是AD和其他神经退行性疾病发生和发展的重要组成部分。在本研究中，通过抑制分子伴侣热休克蛋白90 （Hsp90）靶向tau通路作为一种有希望的影响AD疾病进展的新途径。该提案建立在STTR I期资助下提出和实现的具体目标的基础上——a)进行结构-活性关系研究，以获得脑渗透性Hsp90抑制剂；b)评估生化和细胞Hsp90抑制作用。这些努力产生了新颖的专有Hsp90抑制剂，具有可接受的药物样特性，包括良好的脑浓度。自I期融资结束以来，Yuma Therapeutics已经在小鼠身上获得了早期先导化合物YT-17的药代动力学数据，进一步支持了其药物样特性。II期研究的重点是：a)评估我们的先导化合物在体内转基因tau病小鼠模型中的脑脊液中总tau和磷酸化tau水平、tau神经病理学和行为结果；b)生产一种主要候选药物的活性药物成分（API），并启动体内毒理学研究；c)原料药的配方工作。

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.