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.

项目摘要/摘要候选人是病理学系的医学化学家和兽医病理学家，密歇根州立大学（MSU）的诊断调查。她的研究兴趣着重于准备小分子以擦除阿尔茨海默氏病（AD）中磷酸化tau（p-tau）的聚集和相关的tauopathies，而其他群体则使用重组TAU寻求聚集抑制剂未经翻译后修改。该K08申请将为Jessica Fortin博士提供必要的支持实现5个目标：1）获取有关潜在废除分子的药物特性的知识 p-tau纤维化（ADME：抽象，分布，代谢和极端）； 2）应用知识化学结构的优化； 3）提高对小鼠进行PK/PD研究的技能； 4）集成概念证明的鼠标模型； 5）制定神经科学领域的独立研究计划药物发现区域。实现这些目标并培养药物发现，神经科学和翻译研究，Fortin博士已经召集了理查德博士完成的多学科心理团队 Neubig（主要导师），药物发现与发展的领导者，5位合作者和一名合作者： Edmund Ellsworth博士和Babak Borhan博士，医学化学和有机化学的先驱； Min-博士 Hao Kuo，P-TAU聚集抑制剂分子生物学的先驱； Scott Counts博士，David Morgan博士，尼古拉斯·卡纳（Nicholas Kanaan）沉积。 MSU在多个部门的药物发现方面拥有强大的计划。该项目将使Fortin博士能够构建一项药物发现计划，以抑制P-Tau及其的汇总相关的神经毒性，并将小分子推向药物开发中的临床前研究和证明使用小鼠模型的概念研究。值得注意的是，AIM 1组织领先优化步骤我们药物发现计划的临床前阶段。 AIM 1将允许最好的新型P-TAU聚集抑制剂将推进到更高级别的测试水平，以使用以下内容获得临床前数据：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体外模型的血脑屏障。 AIM 2将评估4个最佳的PK/PD，安全性和脑部通透性在AIM 3中使用的同一小鼠菌株中的化合物作为AIM 3中的概念证明，这是两个最好的小说分子将在转基因小鼠模型中进行长期降低神经退行性的测试（PS19 p301s）。该模型具有筛选程序中使用的相同人类的同工型。这格兰特（Grant）将为Fortin博士提供培训和支持，并将其整合到MSU兽医学院药物，允许对小分子发现和开发提出额外的R01提案 AD和相关tauopathies的治疗剂。这将促进Fortin博士的发展成为独立的神经科学药物发现社区的研究人员和贡献者。