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
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > bromodomain and extraterminal protein
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > small molecules > cofactors
bioinformatics > genomics and proteomics > small molecules > cofactors > ligands
Investigative techniques and equipment > spectroscopy > magnetic resonance spectroscopy
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > small molecules
Investigative techniques and equipment > spectroscopy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
Investigative techniques and equipment > x ray crystallography |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Dos Santos lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: |
Matthew Dunn
|
| Date: |
1 February 2019 |
| Date Deposited: |
05 Feb 2019 20:34 |
| Last Modified: |
02 Feb 2024 16:13 |
| PMCID: |
PMC6374164 |
| Related URLs: |
|
| URI: |
https://repository.cshl.edu/id/eprint/37683 |
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