PROJECT SUMMARY Kennedy’s disease also known as spinobulbar muscular atrophy (SBMA) is a progressive neurodegenerative disease caused by genetic polyglutamine expansion of the androgen receptor (AR). Recent research has shown that the mutant AR protein misfolds, aggregates, and abnormally interacts with other proteins, leading to hormone-dependent lower motor neuron degeneration and skeletal muscle atrophy. Currently, there are no treatments available to stop or slow the progression of SBMA, therefore, there is dire unmet medical need to discover novel therapeutic agents. The AR pathway is currently a very important area being studied in SBMA. Experimental studies for the treatment of SBMA have focused on interaction of the AR with testosterone. Removal of testosterone in animal models through castration appears to be protective and potentially restores some lost function. Knockout of AR in SBMA patient-derived stem cells differentiated into neurons reverse the neurotoxic effects of the mutant AR. This led to the use of antiandrogenic therapies for the SBMA treatment. Our objective is to evaluate novel selective AR degraders (SARDs) using preclinical models for the treatment of SBMA and evaluate their mechanism of action. Design, synthesis, characterization, and structure-activity relationship studies of approximately 60 AR-targeting small molecules provided necessary information to advance to the next stage of structure activity relationship (SAR) optimization. The SARDs have been extensively studied in advanced prostate cancer (PCa) models. Importantly, the SARDs, unlike any other molecule targeting the AR, bind to the AR activation function-1 (AF-1) domain in the N-terminus domain (NTD) region and degrade the AR via the ubiquitin/proteasome pathway. The SARDs are orally bioavailable with pharmacokinetic (PK) and drug-like properties suitable for further optimization. The molecules also exhibited excellent efficacy in vivo SBMA model. In this application, we will perform SAR studies to identify and optimize a molecule that is effective against SBMA in vitro (aim-1) and in vivo (aim 2) models at much lower concentrations than the 1st generation molecules. We will also perform studies to elucidate the mechanism of action of SARDs and AR (aim 3) in SBMA. We have put together an outstanding team that has extensive experience in hormone receptor and musculoskeletal research (Dr. Narayanan), AR medicinal chemistry (Dr. Miller), stem cell biology (Dr. Johnson), animal neurobehavior (Dr. Mulligan), and pharmacokinetics (Dr. Tan).