Kirberger, S. E., Ycas, P. D., Johnson, J. A., Chen, C., Ciccone, M. F., Woo, R. W. L., Urick, A. K., Zahid, H., Shi, K., Aihara, H., McAllister, S. D., Kashani-Sabet, M., Shi, J., Dickson, A., Dos Santos, C. O., Pomerantz, W. C. K. (February 2019) Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor. Org Biomol Chem, 17 (2). pp. 2020-2027. ISSN 1477-0520
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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > bromodomain and extraterminal protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor |
| CSHL Authors: | |
| Communities: | CSHL labs > Dos Santos lab |
| Depositing User: | Matthew Dunn |
| Date: | 1 February 2019 |
| Date Deposited: | 05 Feb 2019 20:34 |
| Last Modified: | 25 Mar 2019 15:02 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/37683 |
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