Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor. Issue 7 (1st February 2019)

• Record Type: Journal Article
• Authors: Kirberger, Steven E.; Ycas, Peter D.; Johnson, Jorden A.; Chen, Chen; Ciccone, Michael F.; Woo, Rinette W. L.; Urick, Andrew K.; Zahid, Huda; Shi, Ke; Aihara, Hideki; McAllister, Sean D.; Kashani-Sabet, Mohammed; Shi, Junwei; Dickson, Alex; dos Santos, Camila O.; Pomerantz, William C. K.
• Is Part Of: Organic & biomolecular chemistry. Volume 17:Issue 7(2019)
• Page Start: 2020
• Page End: 2027
• Publication Date: 2019-02-01
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c8ob02599a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : 19 F NMR-guided development of a BPTF chemical probe through SAR and ligand deconstruction. 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.