Caspase-2 (Casp2) has been described in the literature as an excellent target for Alzheimer's disease (AD) and has been implicated as therapeutically relevant in Huntington's disease (HD). Several non-apoptotic roles of Casp2 that may be relevant to neurotherapeutic discovery include its regulation of autophagy, oxidative stress, endoplasmic reticulum stress, and its effect on dendritic spines. Our own collaborative work provides evidence that ?tau314 (a non-fibillar, N-terminal tau fragment) levels are correlated with AD in humans. In rTg4510 mice, which express the hP301L tau associated with frontotemporal dementia (FTD), we have shown that Casp2 cleaves tau to form ?tau314 (H2N?YKPVD314), a heretofore-unreported tau fragment, and have linked this soluble tau fragment to reversible cognitive dysfunction. Given these exciting and promising results, we have initiated a comprehensive program to identify potent and selective Casp2 inhibitors. This platform includes standard structure-based design of covalent inhibitors based on the YKPVD314 cleavage site in tau and high-throughput screening (HTS). Herein we propose to employ fragment-based screening (FBS) to expand and complement the scope of this program, increasing the likelihood we will discover small-molecule inhibitors of Casp2. The single specific aim of this exploratory project is to identify and characterize fragments (low molecular weight and soluble compounds) that bind to Casp2. A commercial in-house fragment library will be screened against Casp2 using differential scanning fluorimetry (DSF). Active ligands will be characterized by surface plasmon resonance (SPR) and X-ray crystallography. Confirmed actives will be validated using SAR (structure-activity relationship) by commerce. Our working hypothesis is that the collection of well- characterized scaffolds we discover will constitute excellent starting points for future work focusing on the optimization and development of potent and selective small-molecule inhibitors of Casp2. The potential impact of this project on human health is considerable. There is an unmet medical need for therapeutic agents that can halt or reverse the cognitive decline associated with AD. This work will have a positive impact on the field of therapeutics to treat the cognitive decline observed in several diseases of the central nervous system, particularly AD, HD, and FTD. The eventual development of a selective inhibitor of Casp2 would address this unmet medical need and would represent a significant advancement in the field of AD.

Public Health Relevance

This work targets the therapeutic inhibition of an enzyme (caspase-2) that promotes the formation of a neurotoxic fragment of tau that is not confined to the tangles that are generally viewed as the hallmarks of AD. This research will provide an excellent foundation for the potential discovery of new drugs able to halt or reverse the devastating cognitive decline associated with Alzheimer?s disease (AD), Huntington?s disease (HD) and frontotemporal dementia (FTD).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG055037-02
Application #
9458089
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Refolo, Lorenzo
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2018-04-15
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455