Approximately 174,000 men in the United States were diagnosed with prostate cancer (PCa) and 31,000 died of PCa in 2019. The number of PCa survivors is expected to increase from 3.3 million men currently to 4.5 million by 2026. One of the primary reasons for treatment failure and castration-resistant prostate cancer (CRPC) relapse is expression of constitutively-active AR splice variants (AR-SVs) that lack the ligand binding domain (LBD) and thus remain constitutively active. AR-SVs contribute to an aggressive phenotype of CRPC, shorter progression-free survival (PFS), and failure to respond to LBD-binding antagonists, enzalutamide or abiraterone. In the parent application, we proposed to discover N-terminus domain (NTD)-binding selective AR degraders (SARDs) as a next-generation treatment for advanced PCa. In the first two years of the parent grant, we serendipitously discovered new set of reagents that bind to the NTD covalently. Our central hypotheses are that the covalently-binding AR inhibitors will serve as the next-generation therapeutics and as a research reagent that will help us to precisely identify the binding site of our SARDs to the AR NTD. To address these hypotheses, we will synthesize covalent molecules that bind strongly and with smaller dissociation constant (kd) for further development for clinical use (specific aims-1 and 2) and use covalent molecules to precisely identify the binding sites of the SARDs and the structure of the AF-1 (specific aim-3). All these studies will help us to increase the impact of the parent grant application, increase the significance of the molecules that are discovered in our parent grant application, and discover new advanced therapeutics. The data will be a harbinger for future development of drugs and diagnostic reagents for the treatment and diagnosis of advanced PCa.