Project Summary/Abstract Alzheimer’s disease (AD) is the most common cause of dementia and currently there is no effective treatment. The amyloid cascade of increased production of amyloid β (Aβ) peptides from amyloid precursor protein (APP) and extracellular deposition in Aβ plaques plays a key role in the pathogenesis and progression of AD. Many disease-modifying therapies have been developed to reduce Aβ production using APP secretase inhibitors and remove extracellular Aβ from brains by Aβ-targeted monoclonal antibodies. While hundreds of clinical trials of these drugs have failed, recently new Aβ-targeted monoclonal antibodies such as donanemab were reported to reduce Aβ in brain and slow cognitive decline in a fraction of AD patients, a vindication for amyloid cascade as a therapeutic target in AD. In this project, we propose to develop the small-molecule degraders of APP as novel amyloid cascade modifying therapeutics. Targeted protein degradation is revolutionizing drug discovery from small-molecule inhibitors to degraders that recruit disease-causing proteins to the proteasomal and lysosome for destruction. Recently we have discovered the compounds as the first APP degraders that degrade APP and thereby reduces Aβ production using the induced pluripotent stem cells (iPSCs) collected from AD patients. APP degrader compounds directly bind at the interface of APP and cytoplasmic activation/ proliferation-associate protein 1 (CAPRIN1) and induce CAPRIN1-mediated APP degradation in the lysosome, resulting in the reduction of neuronal production and extracellular accumulation of Aβ amyloids in AD iPSC neurons and organoids. In this STTR phase I project, we propose to optimize APP degrader compounds with the objective of identifying more lead compounds with improved potency, solubility, and permeability of blood-brain barrier (BBB). To achieve this objective, we propose a hit-to-lead optimization with the focus on chemical modifications of our lead compounds by our state-of-the art computational chemistry approaches in Aim 1. Each compound will be designed based on computer-predicted drug-like properties and BBB permeability and advanced through our compound testing funnel of step-by-step assays of the activity and drug-like properties. The activity in reduction of APP and Aβ will be confirmed in our panel of AD patients’ iPSCs. The top-ranked potent compounds will be selected from the studies of Aim 1 and subjected to pharmacokinetic and therapeutic evaluation in AD mouse models to determine whether the compound treatment improves mouse learning task and reduces APP and Aβ levels and Aβ plaques in AD mouse brains. Upon completion of this one-year project, we expect to provide a proof-of-concept that the small molecule degraders of APP can be used to treat AD mouse models through the degradation of APP and reduction of Aβ42 in AD brains. Therefore, this STTR phase I grant will support us to move the project from the hit-to-lead to lead optimiza...