Alzheimers disease (AD) affects more than 5M Americans today, and is the most common cause of dementia in adults. While current medications slightly delay symptoms, no medications exist to cure or stop disease progression. A current focus at NIA is to identify novel drug targets, that address resilience to AD; also, there is an increasing perspective at NIA that Multi-target therapy may be necessary to overcome AD. We present the novel drug target Shc, which was recently shown to be a major resilience factor in conversion from human MCI to AD1, and whose activity rises in AD hippocampus2. Also, PSAPP mice with genetically decreased Shc protein had increased cognitive function and memory and survival, with the same burden of plaques and tangles-- thus Shc reduction represents a novel target whose reduction enables a neuroprotective 'resilience' mechanism3. Mice with genetic Shc deficiency are also protected from age related cerebrovascular dysfunction4 ALS5 and MS6, so reduction of Shc activity increases neuroprotection and resilience in multiple neurodegenerative conditions. To try to mimic the demonstrated neuroprotective benefit of genetic Shc reduction with a small molecule, we started with a repurposing approach to isolate 6 chemical scaffolds with Shc blocking activity7. Then a novel 3- dimensional scaffold search was carried out to identify 400 new molecules on completely novel scaffolds. These 400 have been winnowed down to a flock of 40 molecules through screening paradigms described in the application and tested them in 20 HTS assays to confer neural cell resistance to amyloid beta and picked the 5 most neuroprotective. PK experiments on the 2 most neuro-protective revealed a better brain penetrance of one molecule. Thus Buto's Aims are (1) to identify the Maximum Tolerated Dose (MTD) of this molecule, 2) to determine Brain and Blood PBMC target engagement in a mouse model of oxidative stress, and 3) to determine efficacy in the 5XFAD and ApoE4 mouse model. These Aims, once achieved, will determine the extent to which molecules that hit a completely novel and never-drugged AD target Shc, are acceptable pre-clinical pharmacological candidates, and set the stage for further partnering of Shc inhibitors in this indication. Public Health Relevance Statement Narrative. Alzheimers disease (AD) causes dementia in >5M Americans. A current focus at NIA is to identify novel drug targets, that address resilience to AD; also, there is an increasing perspective at NIA that Multi-target therapy may be necessary to overcome AD. We focus on small-molecule Shc blockers that increase resilience to A-beta and other insults. We propose in vivo MTD and efficacy studies in the 5XFAD and ApoE4 mouse model of our lead compound.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Aging ; 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 ; Animals ; inhibitor/antagonist ; inhibitor ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood ; Blood Reticuloendothelial System ; Brain ; Brain Nervous System ; Encephalon ; Cells ; Cell Body ; Diet ; diets ; Animal Disease Models ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Human ; Modern Man ; Inflammation ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Memory ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Drug Kinetics ; Pharmacokinetics ; Clinical Pharmacology ; Phosphorylation ; Protein Phosphorylation ; Proteins ; Insulin Receptor ; Insulin Receptor Protein-Tyrosine Kinase ; Insulin-Dependent Tyrosine Protein Kinase ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Synapses ; Synaptic ; synapse ; Testing ; Tyrosine ; apolipoprotein E-4 ; APOE e4 ; APOE-ε4 ; APOEε4 ; apo E-4 ; apo E4 ; apo epsilon4 ; apoE epsilon 4 ; apoE-4 ; apoE4 ; apolipoprotein E epsilon 4 ; apolipoprotein E4 ; Phosphotyrosine ; Tyrosine-O-phosphate ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Neurotrophic Tyrosine Kinase Receptor Type 2 ; BDNF Receptor ; BDNF/NT-3 Growth Factors Receptor ; Brain-Derived Neurotrophic Factor Receptor ; GP145-TRKB ; NTRK2 Receptor ; TRKB Tyrosine Kinase ; trkB Receptor ; trkB(gp145) Protein ; Neurofibrillary Tangles ; neurofibrillary degeneration ; neurofibrillary lesion ; neurofibrillary pathology ; tangle ; Brain-Derived Neurotrophic Factor ; BDNF ; TimeLine ; Biological ; Chemicals ; Measurement ; Development Plans ; Oxidative Stress ; Disease Progression ; Therapeutic ; Metabolic ; Genetic ; Inflammatory ; scaffolding ; scaffold ; cognitive function ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Amentia ; Dementia ; Penetrance ; American ; neuroprotection ; object recognition ; PBMC ; Peripheral Blood Mononuclear Cell ; Toxicities ; Toxic effect ; Therapeutic Index ; cognitive defects ; Cognitive deficits ; novel ; MMAC1 ; Mutated in Multiple Advanced Cancers 1 ; PHTS gene ; PHTS protein ; PTEN ; PTEN Hamartoma Tumor Syndrome ; PTEN Hamartoma Tumor Syndrome With Granular Cell Tumor ; PTEN1 ; Phosphatase and Tensin Homolog ; Phosphatase and Tensin Homolog Deleted on Chromosome 10 ; PTEN gene ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; response ; drug development ; Molecular Interaction ; Binding ; small molecule ; HIRS-1 ; IRS1 ; IRS1 gene ; PI3CG ; PI3KGamma ; PI3k ; PIK3 ; PIK3CG ; PIK3CG gene ; Address ; Dose ; Defect ; Symptoms ; fear conditioning ; conditioned fear ; in vivo ; Text ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; cerebrovascular ; cerebral vascular ; cerebro-vascular ; age related ; age dependent ; neurobehavioral ; knock-down ; knockdown ; three-dimensional modeling ; 3-D modeling ; 3D modeling ; insulin sensitizing drugs ; insulin sensitizer ; resilience ; Resistance ; resistant ; mouse model ; murine model ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; screening ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; Growth Factor ; Growth Agents ; Growth Substances ; Proteins Growth Factors ; experimental study ; experiment ; experimental research ; efficacy study ; in silico ; blood-brain barrier penetration ; BBB penetration ; bloodbrain barrier penetration ; Alzheimer's disease therapeutic ; Alzheimer's therapeutic ;
