Small molecule inhibitors of hyperphosphorylated tau aggregation in Alzheimer's disease: lead optimization, and proof of concept in a rodent model

阿尔茨海默病中过度磷酸化 tau 蛋白聚集的小分子抑制剂：先导化合物优化和啮齿动物模型中的概念验证

基本信息

批准号：
10621755
负责人：
Jessica Fortin
金额：
$ 16.42万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

项目摘要

Project Summary/Abstract The candidate is a medicinal chemist and veterinary pathologist in the Department of Pathobiology and Diagnostic Investigation at Michigan State University (MSU). Her research interests focus on the preparation of small molecules to abrogate the aggregation of hyperphosphorylated tau (p-tau) in Alzheimer’s disease (AD) and related tauopathies, while other groups have sought aggregation inhibitors using recombinant tau that was not post-translationally modified. This K08 application will provide Dr. Jessica Fortin with the support necessary to accomplish 5 goals: 1) to gain knowledge on the pharmaceutical properties of potent abrogating molecules of p-tau fibrillization (ADME: absorption, distribution, metabolism, and excretion); 2) to apply knowledge for optimization of chemical structures; 3) to advance skills in conducting PK/PD studies in mice; 4) to integrate a mouse model for proof of concept studies; 5) to develop an independent research program in the neuroscience area of drug discovery. To achieve these goals and foster expertise in drug discovery, neuroscience, and translational research, Dr. Fortin has assembled a multi-disciplinary mentoring team comprised of Dr. Richard Neubig (primary mentor), a leader in drug discovery and development, and 5 co-mentors and one collaborator: Dr. Edmund Ellsworth and Dr. Babak Borhan, pioneers in medicinal chemistry and organic chemistry; Dr. Min- Hao Kuo, a pioneer in molecular biology of p-tau aggregation inhibitors; and Dr. Scott Counts, Dr. David Morgan, and Dr. Nicholas Kanaan (collaborator), pioneers in the design of translational studies using animal model of tau deposition. MSU has strong programs in drug discovery in multiple Departments. This project will enable Dr. Fortin to build a drug discovery program to inhibit aggregation of p-tau and its associated neurotoxicity, and propel small molecules to preclinical studies in drug development and proof of concept studies using a mouse model of tauopathies. Notably, Aim 1 organizes lead optimization steps prior to the preclinical stage of our drug discovery program. Aim 1 will allow the best novel p-tau aggregation inhibitors to be propelled to a higher level of testing to obtain preclinical data using the following: solubility test, protein binding assay, Caco-2 cell culture, P-glycoprotein substrate and inhibition assay, microsomal stability assay, and a blood-brain barrier in vitro model. Aim 2 will evaluate PK/PD, safety, and brain permeability of 4 best compounds in the same mouse strain to be used in Aim 3. As a proof of concept in Aim 3, the two best novel molecules will be tested for long-term reduction of neurodegeneration in a transgenic mouse model (PS19 P301S) of tauopathies. The model harbors the same human tau isoform used in the screening program. This grant will provide the training and support for Dr. Fortin to be integrated into the MSU College of Veterinary Medicine, allowing for an additional R01 proposal for the discovery and development of small molecule therapeutics in AD and related tauopathies. This will facilitate Dr. Fortin’s development into an independent researcher and contributor in the neuroscience drug discovery community.

项目概要/摘要候选人是病理生物学系的药物化学家和兽医病理学家她在密歇根州立大学 (MSU) 从事诊断调查工作，研究兴趣集中在准备工作上。小分子可消除阿尔茨海默病 (AD) 中过度磷酸化 tau (p-tau) 的聚集和相关的 tau 蛋白病，而其他研究组则在寻找使用重组 tau 蛋白的聚集抑制剂，未进行翻译后修改。此 K08 应用程序将为 Jessica Fortin 博士提供必要的支持。实现 5 个目标：1) 获得有关有效废除分子的药物特性的知识 p-tau 纤维化（ADME：吸收、分布、代谢和排泄）2）应用知识；优化化学结构；3) 提高在小鼠中进行 PK/PD 研究的技能；用于概念验证研究的小鼠模型；5) 开发神经科学领域的独立研究项目为了实现这些目标并培养药物发现、神经科学和药物发现领域的专业知识。在转化研究方面，Fortin 博士组建了一支由 Richard 博士组成的多学科指导团队 Neubig（主要导师），药物发现和开发领域的领导者，以及 5 名共同导师和 1 名合作者：药物化学和有机化学领域的先驱 Edmund Ellsworth 博士和 Babak Borhan 博士；郭浩 (Hao Kuo)，p-tau 聚集抑制剂分子生物学先驱；Scott Counts 博士、David Morgan 博士、和 Nicholas Kanaan 博士（合作者），利用 tau 动物模型设计转化研究的先驱密歇根州立大学在多个部门都有强大的药物发现项目。该项目将使 Fortin 博士能够建立一个药物发现计划来抑制 p-tau 及其聚集相关的神经毒性，并推动小分子进行药物开发和证明的临床前研究使用 tau蛋白病小鼠模型进行概念研究值得注意的是，目标 1 在之前组织了先导优化步骤。我们药物发现计划的临床前阶段目标 1 将开发出最好的新型 p-tau 聚集抑制剂。使用以下方法推进到更高水平的测试以获得临床前数据：溶解度测试、蛋白质结合测定、Caco-2 细胞培养、P-糖蛋白底物和抑制测定、微粒体稳定性测定和血脑屏障体外模型将评估 4 个最佳药物的 PK/PD、安全性和脑通透性。目标 3 中使用的同一小鼠品系中的化合物。作为目标 3 中的概念证明，两个最好的新颖将在转基因小鼠模型（PS19 P301S）的 tau 蛋白病。该模型具有与筛选程序中使用的相同的人类 tau 亚型。赠款将为 Fortin 博士提供培训和支持，帮助他融入密歇根州立大学兽医学院医学，允许额外的 R01 提案用于小分子的发现和开发 AD 和相关 tau蛋白病的治疗方法将有助于 Fortin 博士发展成为一名独立的医生。神经科学药物发现界的研究员和贡献者。