Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor

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Kirberger, S. E., Ycas, P. D., Johnson, J. A., Chen, C., Ciccone, M. F., Woo, R. W. L., Urick, A. K., Zahid, H., Shi, K., Aihara, H., McAllister, S. D., Kashani-Sabet, M., Shi, J., Dickson, A., Dos Santos, C. O., Pomerantz, W. C. K. (February 2019) Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor. Org Biomol Chem, 17 (2). pp. 2020-2027. ISSN 1477-0520

URL: https://www.ncbi.nlm.nih.gov/pubmed/30706071

DOI: 10.1039/c8ob02599a

Abstract

Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > bromodomain and extraterminal protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Dos Santos, Camila O. Chen, Chen Ciccone, Michael F
Communities:	CSHL labs > Dos Santos lab CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User:	Matthew Dunn
Date:	1 February 2019
Date Deposited:	05 Feb 2019 20:34
Last Modified:	29 Jun 2021 19:34
PMCID:	PMC6374164
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/37683

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