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

• 批准号: 10371380
• 负责人: Jessica Fortin
• 金额: $ 16.42万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10371380
• 关键词: ABCB1 gene; Acute; Age-Months; Alzheimer' s Disease; Alzheimer' s disease related dementia; Ames Assay; Animal Model; Area; Behavior; Binding Proteins; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Caco-2 Cells; Cell Culture Techniques; Cell Death; Chemical Structure; Chemicals; Cognition; Communities; Cytoprotection; Data; Deposition; Development; Diagnostic; Disease Progression; Dose; Drug Kinetics; Ensure; Equilibrium; Excretory function; Fostering; Genetic; Goals; Grant; Human; Impaired cognition; In Vitro; Intestinal Absorption; Intraperitoneal Injections; Investigation; Knowledge; Language; Link; MAPT gene; Measures; Mentors; Metabolism; Michigan; Modeling; Molecular Biology; Mouse Strains; Movement; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurosciences; Neurosciences Research; Organ; Organic Chemistry; Pathologic; Pathologist; Permeability; Pharmaceutical Chemistry; Pharmacologic Substance; Plasma; Preclinical Testing; Preparation; Property; Protein Isoforms; Recombinants; Research; Research Personnel; Rodent Model; Safety; Senile Plaques; Solubility; Tauopathies; Technology; Testing; Time; Tissues; Toxicology; Training Support; Transgenic Mice; Transgenic Organisms; Translational Research; Universities; Veterinary Medicine; absorption; blood-brain barrier permeabilization; college; cytotoxicity; design; drug development; drug discovery; efficacy study; hydrophilicity; hyperphosphorylated tau; improved; in vitro Model; in vivo; in vivo evaluation; inhibitor; interest; lead optimization; lipophilicity; mouse model; multidisciplinary; mutant; neurotoxic; neurotoxicity; novel; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; programs; safety assessment; screening program; skills; small molecule; small molecule inhibitor; small molecule therapeutics; spatiotemporal; tau Proteins; tau aggregation; tau-1; translational study

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.

项目总结/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， 密歇根州立大学（MSU）的诊断研究。她的研究兴趣集中在制备 消除阿尔茨海默病（AD）中过度磷酸化tau（p-tau）聚集的小分子 和相关的tau蛋白病，而其他研究小组则使用重组tau蛋白寻找聚集抑制剂， 而不是事后修改。此K 08应用程序将为Jessica Fortin博士提供必要的支持 实现5个目标：1）获得关于有效废除分子的药物特性的知识 p-tau蛋白的吸收、分布、代谢和排泄（ADME：Absorption，Distribution，Metabolism，and Excretion）; 2）将知识应用于 优化化学结构; 3）提高在小鼠中进行PK/PD研究的技能; 4）整合 用于概念验证研究的小鼠模型; 5）开发神经科学领域的独立研究计划 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， 转化研究，福廷博士组建了一个多学科的指导团队，由理查德博士 Neubig（主要导师），药物发现和开发的领导者，以及5名共同导师和一名合作者： 博士Edmund Ellsworth和Babak Borhan博士，药物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，大卫摩根博士， Nicholas Kanaan博士（合作者），使用tau动物模型设计转化研究的先驱 证词MSU在多个部门的药物发现方面有很强的计划。 该项目将使Fortin博士能够建立一个药物发现计划，以抑制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的临床前研究和证据， 使用Tau蛋白病小鼠模型的概念研究。值得注意的是，目标1组织铅优化步骤之前， 我们药物发现项目的临床前阶段目标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：溶解度测试，蛋白质 结合试验、Caco-2细胞培养、P-糖蛋白底物和抑制试验、微粒体稳定性试验，以及 血脑屏障体外模型。目的2将评价4种最佳药物的PK/PD、安全性和脑渗透性 化合物在相同的小鼠品系中用于目标3。作为Aim 3中概念的证明， 分子将在转基因小鼠模型中测试神经变性的长期减少（PS19 P301 S）的tau蛋白病。该模型具有与筛选程序中使用的相同的人tau同种型。这 赠款将为Fortin博士提供培训和支持，使其融入MSU兽医学院 医学，允许额外的R 01提案用于发现和开发小分子 AD和相关Tau蛋白病的治疗剂。这将有助于福廷博士发展成为一个独立的 神经科学药物发现社区的研究员和贡献者。