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.
Public Health Relevance Statement: NARRATIVE Alzheimer's Disease is a particularly cruel neurodegenerative disease due to the often-prolonged duration of patient suffering and its negative impact on cognitive and bodily motor function, resulting in the loss of personal dignity. Alzheimer's Disease afflicts ten percent of people aged 65 and older and currently, there are no effective treatments to cure or even arrest the progression of the disease, leaving a great unmet medical need. ADRx is proposing to develop a small molecule therapeutic to be orally delivered in the form of a pill, that will penetrate the brain and stop the cognitive loss associated with Alzheimer's using novel insight from structural biology. Terms: Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; inhibitor; Antibodies; Binding Sites; Combining Site; Reactive Site; Biological Assay; Assay; Bioassay; Biologic Assays; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Brain; Brain Nervous System; Encephalon; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Clinical Trials; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electrons; Negative Beta Particle; Negatrons; Face; faces; facial; Foundations; Gallic acid; Goals; Hybrids; Intestines; Intestinal; bowel; Lead; Pb element; heavy metal Pb; heavy metal lead; Metabolism; Intermediary Metabolism; Metabolic Processes; Methods; Molecular Structure; Macromolecular Structure; Persons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; Patients; Permeability; Research; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Testing; Time; Translations; United States; Work; Epigallocatechin Gallate; EGCG; EGCG cpd; Epigallocatechingallate; Green Tea Extract; Green Tea Polyphenols; Tea catechin; epigallo-catechin gallate; epigallocatechin-3-gallate; polyphenol; Neurofibrillary Tangles; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; tangle; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; Family Caregiver; Family Care Giver; Family member; base; density; Site; Phase; Medical; Series; Chemicals; Evaluation; Failure; insight; brain atrophy; cortical atrophy; cerebral atrophy; Disease Progression; Therapeutic Agents; Metabolic; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aß plaques; cored plaque; diffuse plaque; Senile Plaques; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Impaired cognition; Complex; Oral; Clinic; Amentia; Dementia; extracellular; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; 65+ years old; Aged 65 and Over; age 65 and greater; age 65 and older; aged 65 and greater; aged â¥65; old age; human old age (65+); structural biology; Cryo-electron Microscopy; Electron Cryomicroscopy; cryo-EM; cryoEM; Cryoelectron Microscopy; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuron loss; pharmacophore; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; Structure; novel; economic impact; Property; drug development; Tauopathies; tau associated neurodegeneration; tau associated neurodegenerative process; tau induced neurodegeneration; tau mediated neurodegeneration; tau neurodegenerative disease; tau neuropathology; tauopathic neurodegenerative disorder; tauopathy; pill; Molecular Interaction; Binding; Biota; small molecule; Incubated; Motor; in vivo; Cognitive; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; Characteristics; Docking; Image; imaging; tau aggregation; abnormally aggregated tau protein; filamentous tau inclusion; microtubule associated protein tau aggregation; microtubule associated protein tau deposit; paired helical filament of tau; self-aggregate tau; tau PHF; tau accumulation; tau aggregate; tau fibrillization; tau filament; tau neurofibrillary tangle; tau oligomer; tau paired helical filament; tau polymerization; tau-tau interaction; Ï aggregation; design; designing; effective therapy; effective treatment; in vitro activity; drug candidate; phase 1 study; Phase I Study; screening; Drug Targeting; small molecule therapeutics; Alzheimer's disease related dementia; AD related dementia; ADRD; Alzheimer related dementia; pharmacokinetics and pharmacodynamics; PK/PD; in silico; blood-brain barrier penetration; BBB penetration; bloodbrain barrier penetration; Alzheimer's disease therapeutic; Alzheimer's therapeutic
