Selectivity, Ligand Deconstruction, and Cellular Activity Analysis of a BPTF Bromodomain Inhibitor

Overview

Journal Org Biomol Chem

Publisher Royal Society of Chemistry

Specialties Biochemistry
Chemistry

Date 2019 Feb 2

PMID 30706071

Citations 15

Authors

Steven E Kirberger

Peter D Ycas

Jorden A Johnson

Chen Chen

Michael F Ciccone

Rinette W L Woo

Andrew K Urick

Huda Zahid

Ke Shi

Hideki Aihara

Sean D McAllister

Mohammed Kashani-Sabet

Junwei Shi

Alex Dickson

Camila O Dos Santos

William C K Pomerantz

Affiliations

Soon will be listed here.

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.

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