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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

Award Number: K08AG071985
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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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 - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $164,430 )
2026	2026	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	5	4/17/2026	NON-COMPETING CONTINUATION	$164,430
														Subtotal = $164,430

Issue Date FY: 2025 ( Subtotal = $164,430 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	4	6/3/2025	NON-COMPETING CONTINUATION	$164,430
														Subtotal = $164,430

Issue Date FY: 2024 ( Subtotal = $164,221 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	001	3	6/27/2024	NON-COMPETING CONTINUATION	$164,221
2024	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	2	6/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $164,221

Issue Date FY: 2023 ( Subtotal = $164,221 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	2	6/22/2023	NON-COMPETING CONTINUATION	$164,221
														Subtotal = $164,221

Issue Date FY: 2022 ( Subtotal = $164,221 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	1	5/13/2022	NEW	$164,221
														Subtotal = $164,221

Grand Total All Awards = $821,523

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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

Award Number: K08AG071985

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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