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. In recent years years, BPTF has become increasingly identified as a pro-tumorigenic factor, prompting investigations into the molecular mechanisms associated with BPTF function. Despite a druggable bromodomain which engages in protein-protein interactions with acetylated histones, small molecule discovery is at an early stage. Using a protein-based <sup>19</sup>F NMR screen, we reported the first selective 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 as well as serving as a mechanism for reducing c-Myc occupancy on chromatin. Given the challenges of further improving affinity and metabolic stability of AU1 for in vivo studies, 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. Finally, we will report our preliminary cellular data in a breast cancer model system as well synergistic effects with chemotherapeutic drugs. These new inhibitors are envisioned to serve as useful chemical probes of BPTF function but in normal and pathophysiology.

New inhibitors for the nucleosome remodeling factor NURF

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.