New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition.

ABSTRACT: The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potential strategy for its inhibition and the evaluation of its functional significance; however, inhibitor development for BPTF has lagged behind those of other bromodomains. Here we describe the development of pyridazinone-based BPTF inhibitors. The lead compound, BZ1, possesses a high potency (K_d = 6.3 nM) and >350-fold selectivity over BET bromodomains. We identify an acidic triad in the binding pocket to guide future designs. We show that our inhibitors sensitize 4T1 breast

SUBMITTER: Zahid H 

PROVIDER: S-EPMC9012132 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature