Novel pyrano 1,3 oxazine based ligand inhibits the epigenetic reader hBRD2 in glioblastoma.
Acetylation
Binding Sites
Cell Movement
Cell Proliferation
Crystallography, X-Ray
Epigenesis, Genetic
Glioblastoma
/ drug therapy
High-Throughput Screening Assays
Histones
/ chemistry
Humans
Ligands
Models, Molecular
Oxazines
/ chemistry
Protein Binding
Protein Conformation
Protein Domains
Transcription Factors
/ antagonists & inhibitors
Tumor Cells, Cultured
3 oxazine derivative
BRD2
NCI diversity
cell-based assay
crystallography
glioblastoma
pyrano 1
Journal
The Biochemical journal
ISSN: 1470-8728
Titre abrégé: Biochem J
Pays: England
ID NLM: 2984726R
Informations de publication
Date de publication:
26 06 2020
26 06 2020
Historique:
received:
29
04
2020
revised:
27
05
2020
accepted:
02
06
2020
pubmed:
3
6
2020
medline:
1
1
2021
entrez:
3
6
2020
Statut:
ppublish
Résumé
Glioblastoma (GBM) is the most common primary brain malignancy, rarely amenable to treatment with a high recurrence rate. GBM are prone to develop resistance to the current repertoire of drugs, including the first-line chemotherapeutic agents with frequent recurrence, limiting therapeutic success. Recent clinical data has evidenced the BRD2 and BRD4 of the BET family proteins as the new druggable targets against GBM. In this relevance, we have discovered a compound (pyrano 1,3 oxazine derivative; NSC 328111; NS5) as an inhibitor of hBRD2 by the rational structure-based approach. The crystal structure of the complex, refined to 1.5 Å resolution, revealed that the NS5 ligand significantly binds to the N-terminal bromodomain (BD1) of BRD2 at the acetylated (Kac) histone binding site. The quantitative binding studies, by SPR and MST assay, indicate that NS5 binds to BD1 of BRD2 with a KD value of ∼1.3 µM. The cell-based assay, in the U87MG glioma cells, confirmed that the discovered compound NS5 significantly attenuated proliferation and migration. Furthermore, evaluation at the translational level established significant inhibition of BRD2 upon treatment with NS5. Hence, we propose that the novel lead compound NS5 has an inhibitory effect on BRD2 in glioblastoma.
Identifiants
pubmed: 32484211
pii: 225121
doi: 10.1042/BCJ20200339
doi:
Substances chimiques
BRD2 protein, human
0
Histones
0
Ligands
0
Oxazines
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2263-2279Informations de copyright
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.