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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/摘要应聘者是病理生物学系的药物化学家和兽医病理学家密歇根州立大学(MSU)的诊断性调查。她的研究兴趣集中在准备小分子阻断阿尔茨海默病(AD)中过度磷酸化tau(p-tau)的聚集和相关的tau病，而其他研究小组则使用重组tau寻找聚集抑制剂未经翻译后修改。此K08应用程序将为Jessica Fortin博士提供必要的支持要实现5个目标：1)了解有效的清除分子的药学性质 P-tau纤维化(ADME：吸收、分布、代谢和排泄)；2)将知识应用于优化化学结构；3)提高在小鼠身上进行PK/PD研究的技能；4)整合用于概念验证研究的小鼠模型；5)在神经科学领域开发独立的研究计划药物发现领域。为了实现这些目标并培养药物发现、神经科学和翻译研究，Fortin博士组建了一个由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： Edmund Ellsworth博士和Babak Borhan博士，药物化学和有机化学的先驱；Min博士- 郭浩，p-tau聚集抑制剂分子生物学的先驱；斯科特博士，大卫·摩根博士，和Nicholas Kanaan博士(合作者)，利用tau的动物模型设计翻译研究的先驱证词。密歇根州立大学在多个部门有强大的药物发现计划。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及其受体的聚集相关的神经毒性，并推动小分子药物开发和证据的临床前研究概念研究使用的是小鼠的tauopathy模型。值得注意的是，AIM 1在执行以下步骤之前组织了线索优化步骤我们的药物发现计划的临床前阶段。目标1将允许最好的新型p-tau聚集抑制剂被推进到更高水平的测试，以获得临床前数据，使用以下内容：溶解度测试，蛋白质结合试验、Caco-2细胞培养、P-糖蛋白底物及抑制试验、微球稳定性试验、一种血脑屏障体外模型。目标2将评估PK/PD、安全性和脑通透性4个最佳在目标3中使用相同品系的化合物。作为目标3中概念的证明，两部最好的小说将在转基因小鼠模型(PS19)中测试分子长期减少神经变性的作用 P301S)。该模型含有与筛查程序中使用的相同的人类tau亚型。这格兰特将为Fortin博士整合到密歇根州立大学兽医学院提供培训和支持医学，允许发现和开发小分子的额外R01提案阿尔茨海默病及相关疾病的治疗。这将有助于Fortin博士发展成为一名独立的神经科学药物发现社区的研究员和贡献者。