Discovery of a PCAF Bromodomain Chemical Probe.
Angew Chem Int Ed Engl
; 56(3): 827-831, 2017 01 16.
Article
em En
| MEDLINE
| ID: mdl-27966810
ABSTRACT
The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamilyâ
I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for inâ
vivo use.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Azo
/
Sondas Moleculares
/
Fatores de Transcrição de p300-CBP
/
Descoberta de Drogas
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Hidralazina
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article