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

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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.