TY - JOUR
T1 - Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor
AU - Kirberger, Steven E.
AU - Ycas, Peter D.
AU - Johnson, Jorden A.
AU - Chen, Chen
AU - Ciccone, Michael F.
AU - Woo, Rinette W.L.
AU - Urick, Andrew K.
AU - Zahid, Huda
AU - Shi, Ke
AU - Aihara, Hideki
AU - McAllister, Sean D.
AU - Kashani-Sabet, Mohammed
AU - Shi, Junwei
AU - Dickson, Alex
AU - Dos Santos, Camila O.
AU - Pomerantz, William C.K.
N1 - Publisher Copyright:
© The Royal Society of Chemistry 2019.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1039/c8ob02599a
DO - 10.1039/c8ob02599a
M3 - Article
C2 - 30706071
AN - SCOPUS:85061480713
SN - 1477-0520
VL - 17
SP - 2020
EP - 2027
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 7
ER -
