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