'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics

Abstract. Alzheimer’s 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 andapos;resilienceandapos; 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 Butoandapos;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.Narrative. Alzheimer’s disease (AD) causes dementia in andgt;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.