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

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 (Kd = 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 cancer cells to doxorubicin
but not BPTF knockdown cells, suggesting a specificity to BPTF. Given
the high potency and good physicochemical properties of these inhibitors,
we anticipate that they will be useful starting points for chemical
tool development to explore the biological roles of BPTF.