Structural highlights
Function
BPTF_HUMAN Histone-binding component of NURF (nucleosome-remodeling factor), a complex which catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin. Specifically recognizes H3 tails trimethylated on 'Lys-4' (H3K4me3), which mark transcription start sites of virtually all active genes. May also regulate transcription through direct binding to DNA or transcription factors.
Publication Abstract from PubMed
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.
New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition.,Zahid H, Buchholz CR, Singh M, Ciccone MF, Chan A, Nithianantham S, Shi K, Aihara H, Fischer M, Schonbrunn E, Dos Santos CO, Landry JW, Pomerantz WCK J Med Chem. 2021 Sep 23;64(18):13902-13917. doi: 10.1021/acs.jmedchem.1c01294., Epub 2021 Sep 13. PMID:34515477[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zahid H, Buchholz CR, Singh M, Ciccone MF, Chan A, Nithianantham S, Shi K, Aihara H, Fischer M, Schonbrunn E, Dos Santos CO, Landry JW, Pomerantz WCK. New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition. J Med Chem. 2021 Sep 23;64(18):13902-13917. doi: 10.1021/acs.jmedchem.1c01294., Epub 2021 Sep 13. PMID:34515477 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01294
