RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.
PLoS One
; 8(12): e83190, 2013.
Article
em En
| MEDLINE
| ID: mdl-24391744
ABSTRACT
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Fatores de Transcrição
/
Proteínas Nucleares
/
Apolipoproteína A-I
/
Proteínas Serina-Treonina Quinases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article