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

Zahid, Huda, Buchholz, Caroline R, Singh, Manjulata, Ciccone, Michael F, Chan, Alice, Nithianantham, Stanley, Shi, Ke, Aihara, Hideki, Fischer, Marcus, Schönbrunn, Ernst, Dos Santos, Camila O, Landry, Joseph W, Pomerantz, William CK (September 2021) New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition. Journal of Medicinal Chemistry. ISSN 0022-2623

URL: https://www.ncbi.nlm.nih.gov/pubmed/34515477
DOI: 10.1021/acs.jmedchem.1c01294

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 (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.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Chromatin dynamics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > nucleosome
CSHL Authors:
Communities: CSHL labs > Dos Santos lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 13 September 2021
Date Deposited: 15 Sep 2021 20:22
Last Modified: 15 Sep 2021 20:22
URI: https://repository.cshl.edu/id/eprint/40349

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