There are no treatment options for neurodegenerative diseases such as Alzheimer’s disease (AD). Current treatments only temporarily suppress disease symptoms. We are pioneering a new paradigm in drug discovery that involves activation of the 20S proteasome, which targets specific proteins associated in the pathogenesis of neurodegenerative diseases. The translation of this therapeutic approach has been largely unexplored due to the lack of suitable leads. This work addressed that void. Our lab identified the most potent 20S activator reported to date. The hit compound activates the proteolytic activity of the 20S proteasome (~10 fold!) and induces the degradation of alpha-synuclein and tau (most notable protein involved in the pathogenesis of AD) in vitro and cell culture without affecting normal structured proteins. We hypothesize that optimization focused on both potency and physicochemical properties will allow us to generate the first 20S activator with drug-like properties suitable for in vivo translation of this new therapeutic strategy for neurodegenerative diseases. In this exploratory R21 grant, we will complete a multiparameter optimization effort by (1) hit-to- lead optimization of potency, and (2) physicochemical optimization of the phenothiazine scaffold to generate drug-like candidates with suitable parameters for CNS chemical space. Successful completion of this work will generate suitable drug-like candidates to explore an entirely new therapeutic approach that targets a unique class of proteins still deemed, undruggable.