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

• Published in: Organic & biomolecular chemistry 2019-02, Vol.17 (7), p.22-227
• Main 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
• Format: Article
• Language: English
• Subjects: Antigens, Nuclear; Biological activity; Cancer; Cell Proliferation; Chromatin remodeling; Computer simulation; CRISPR; Crystallography, X-Ray; Deconstruction; Fluorine; Humans; Inhibitors; Ligands; Magnetic Resonance Spectroscopy; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Nerve Tissue Proteins - antagonists & inhibitors; NMR; Nuclear magnetic resonance; Pharmacology; PharmacoPhores; Proteins; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rac1 protein; Selectivity; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Tumor cell lines
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/c8ob02599a

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