ABSTRACT Nuclear receptors are steroid-dependent transcription factors that confer cell identity. They guide development, and maintain homeostasis in adult tissue, such as the testosterone responsive Androgen Receptor which governs male-specific tissues. Aberrant AR-driven gene expression programs give rise to prostate cancer. When resistance arises after androgen-deprivation therapy (ADT) the disease advances to the much more lethal metastatic castration-resistant prostate cancer (mCRPC), becoming resistant to these therapies by overexpressing AR. New evidence suggests that many other transcription factors and epigenetic co-activator proteins may create disease-specific enhancers with the AR to drive tumors, especially in treatment-relapsed mCRPC. As a well-trained synthetic chemist, molecular biologist and computational biologist, I will map the epigenetic mechanisms at work in mCRPC, in new clinically relevant organoid models. I will show how to stop the AR-axis using small molecules I discovered with novel mechanisms of action, where the AR undergoes a chemically induced functional switch, causing the AR to suppress the tumor-driving genes it normally activates. Additionally, I aim to uncover co-dependency epigenetic proteins which drive late stage disease, and use new molecules perturbing CBP/p300 (histone acetyl transferases that build active enhancers) as a strategy to selectively halt the genes driving disease relapse. At the conclusion of this work, we should have the first mechanistic understanding the AR under the influence of an inverse agonist, provide functional epigenetic map of regulatory addictions in advanced PCa, and have explored therapeutic potential of promising new AR therapeutics.