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:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal diseases & disorders > cancer > cancer types > breast cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions 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 organism description > animal > mammal organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > nucleosome organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Dos Santos, Camila O.
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:	26 Jan 2024 16:49
PMCID:	PMC9012132
URI:	https://repository.cshl.edu/id/eprint/40349

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