Protein members of nucleosome remodeling complexes are emerging therapeutic targets. One protein of interest, the Bromodomain PHD Finger Transcription Factor, BPTF, is an essential member of the human nucleosome remodeling factor NURF. BPTF has become increasingly identified as a pro-tumorigenic factor, prompting investigations into the molecular mechanisms associated with BPTF function. We recently validated the druggability of the BPTF bromodomain using a protein-based 19F NMR fragment screen, and reported the first inhibitor of the BPTF bromodomain, AU1, which was selective over the highly druggable BRD4 protein. This molecule demonstrated the importance of the bromodomain for mediating transcription and provided a mechanism for reducing c-Myc occupancy on chromatin. Despite preliminary studies showing in vivo activity, further development has been limited by poor physicochemical properties and modest potency of AU1. We now report several new inhibitors with increased potency for BPTF. We will describe our medicinal chemistry efforts using structure-based design to improve affinity and selectivity, as well as highlight the first small molecule cocrystal structures to help explain the origins of selectivity and demonstrate synergistic effects with chemotherapeutic drugs in a triple negative breast cancer model. In our newest efforts towards pediatric cancers, I will also describe our progress towards developing first in class BPTF degraders. These new inhibitors and degraderss are envisioned to serve as useful chemical probes of BPTF function both in normal and pathophysiology.