Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor.
Org Biomol Chem
; 17(7): 2020-2027, 2019 02 13.
Article
en En
| MEDLINE
| ID: mdl-30706071
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Piridinas
/
Factores de Transcripción
/
Bibliotecas de Moléculas Pequeñas
/
Proteínas del Tejido Nervioso
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Org Biomol Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido