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

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:
Communities: CSHL labs > Dos Santos lab
Depositing User: Matthew Dunn
Date: 1 February 2019
Date Deposited: 05 Feb 2019 20:34
Last Modified: 25 Mar 2019 15:02
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37683

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