Discovery of
Animals
Cell Cycle Proteins
/ antagonists & inhibitors
Drug Discovery
/ methods
Female
HeLa Cells
Humans
Mice
Mice, SCID
Protein Domains
/ drug effects
Protein Structure, Secondary
Protein Structure, Tertiary
Pyridines
/ chemistry
Pyrroles
/ chemistry
Transcription Factors
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
/ methods
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
28 05 2020
28 05 2020
Historique:
pubmed:
24
4
2020
medline:
24
10
2020
entrez:
24
4
2020
Statut:
ppublish
Résumé
The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound
Identifiants
pubmed: 32324999
doi: 10.1021/acs.jmedchem.0c00628
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Pyridines
0
Pyrroles
0
Transcription Factors
0
ABBV-744
9MX546E2SF
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM