Monday, April 28, 2025
4/28/2025
Brain-penetrant chemical disaggregators of tau fibrils as therapeutics for Alzheimer's Disease - ABSTRACT Alzheimer’s disease is a multifactorial disease in which numerous mechanisms culminate in neuronal death, brain atrophy and progressive dementia. The duration of Alzheimer’s disease-related dementia makes Alzheimer’s disease particularly pernicious; exacerbating the suffering of patients who live for nearly a decade as their brain matter slowly and irreversibly dies, and the suffering of family members and caregivers who helplessly stand by. The long duration also exacts a tremendous economic impact, which, in 2020 will amount to some $305 billion in the United States alone. Numerous therapies have been tested in clinical trials, yet as of today there is no treatment to effectively cure, or even slow the progression of Alzheimer’s disease, leaving a great unmet medical need. The accumulation of fibrillar aggregates -- extracellular plaques of Amyloid beta and intraneuronal tangles of tau -- are the defining characteristics of Alzheimer’s disease. However, with imaging and neuropathological studies overwhelmingly showing that plaque density correlates poorly with cognitive decline along with recent failures of drug development targeting Amyloid-beta plaques , the field is now shifting very quickly to focus on tau. Antibodies targeted against tau are now being evaluated in clinical trials; however, they face challenges in their ability to enter the brain and gain access into the neurons where aggregation takes place. Conversely, small molecules that can target aggregated tau directly within the neurons have been a great challenge to develop because of the difficulties in establishing a specific and well-defined binding site on the tau aggregates, and hence a clear mechanism of action. For the first time, a clear binding site has been described on AD-tau fibrils using cryoEM. It has been shown that the EGCG molecule bound to that site can disaggregate those fibrils with a structural explanation of this activity. Based on those preliminary studies, the proposed project encompasses a strategy in which ADRx will use the defined EGCG pharmacophore and expand the chemical matter screened against that entity first through in silico methods and then through experimental evaluation of hits. Our goal is to emerge from Phase 1 studies with structures of molecular complexes of AD-tau fibrils with 2-3 lead compounds with high potencies for AD-tau disaggregation, and promising drug-like properties (good metabolic stability and BBB penetration). In Phase 2 of the SBIR, we will refine these lead compounds and optimize potency and drug-likeness through a series of steps, using principles of medicinal chemistry and structure-based design, to show proof-of-efficacy in animal models of tauopathy. This proof-of-efficacy will provide the foundation for further optimization of these leads into drug candidates, and ultimately a translation of a structure-based AD-Tau disaggregant into the clinic.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).