biostudies-literatureZahid HNCRR NIH HHSNIA NIH HHSAmerican Lebanese Syrian Associated CharitiesNational Institutes of HealthNational Institute of General Medical SciencesNational Institute on AgingCold Spring Harbor LaboratoryNorthwell Health AffiliationUniversity of MinnesotaU.S. Department of DefenseNational Cancer InstituteNCI NIH HHSNIGMS NIH HHS13902-13917https://www.ebi.ac.uk/biostudies/studies/S-EPMC9012132biostudies-literatureUnknown64(18)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, <b>BZ1</b>, possesses a high potency (<i>K</i>_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 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.Journal of medicinal chemistryNew Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition.PMC9012132P30 GM124165R01CA248158-01R35 GM142772W81XWH1910489R35GM140837-01T32 GM132029R35GN142772-01R01R01 AG069727P30 CA045508R01 GM121414R35 GM118047S10 RR029205R01 CA248158R01GM121414-04R35 GM140837P30 CA076292Zahid HAihara HChan ALandry JWPomerantz WCKDos Santos COSchonbrunn EBuchholz CRCiccone MFSingh MFischer MNithianantham SShi KfalseNew 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, <b>BZ1</b>, possesses a high potency (<i>K</i>_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 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.2021-01-01T00:00:00Z2021 Sep2026-05-31T02:15:30.788Z2025-04-04T21:00:52.656ZS-EPMC90121323451547710.1021/acs.jmedchem.1c01294