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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.

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Department of Chemistry, University of Minnesota, 207 Pleasant St. SE., Minneapolis, MN 55455, USA.


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.

[Available on 2020-02-13]
[Indexed for MEDLINE]

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