Development of orally bioavailable and blood-brain barrier penetrant, small molecule TAK1 inhibitors as a novel treatment for Alzheimer's Disease

PROJECT SUMMARY / ABSTRACT The Phase I STTR grant proposal aims to address the escalating global health challenge posed by Alzheimer's disease (AD) by targeting TAK1 as a novel drug target. Currently, there is a lack of effective therapies to slow or prevent disease progression. Identification of new drug targets involved in the pathogenesis of AD is essential to expand treatment options and identify therapies that have the potential to improve the lives of AD patients. In collaboration with Dr. Jun Ninomiya-Tsuji at North Carolina State University, this Phase I STTR builds on our foundational studies that demonstrate the therapeutic potential of targeting TAK1. Our preliminary studies shave shown that TAK1 phosphorylation (activation of the kinase) is significantly upregulated in aged WT and APP/PS1 mice, and that conditional TAK1 knockout in hippocampal neurons significantly reduces cognitive decline in this mouse model. Further validation in the PS19 tauopathy model showed that TAK1 KO reduced neuronal death in the dorsal dentate gyrus, indicating TAK1 is a critical mediator of non-canonical signaling within neurons and can regulate neuronal necroptosis in AD mouse models. These foundational observations lay the groundwork for this Phase I STTR. Utilizing EydisBio’s patented first-in-class TAK1 inhibitors, this proposal will identify suitable TAK1 inhibitors with optimal central nervous system blood-brain barrier penetrance that can be further advanced into in vivo testing in the PS19 mouse model. Successful outcomes of this proposal would be the identification of at least 1 pre-clinical candidate that demonstrates optimal target product profile attributes for further advancement into efficacy and IND-enabling safety studies using funds provided by the NIH through a Phase II SBIR/STTR grant.