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Org Biomol Chem. 2019 Feb 13;17(7):2020-2027. doi: 10.1039/c8ob02599a.

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

Author information

1
Department of Chemistry, University of Minnesota, 207 Pleasant St. SE., Minneapolis, MN 55455, USA. wcp@umn.edu.

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.

PMID:
30706071
PMCID:
PMC6374164
[Available on 2020-02-13]
DOI:
10.1039/c8ob02599a
[Indexed for MEDLINE]

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