Target-based approach to inhibitors of histone arginine methyltransferases.
J Med Chem
; 50(10): 2319-25, 2007 May 17.
Article
em En
| MEDLINE
| ID: mdl-17432842
ABSTRACT
Lysine and arginine methyltransferases participate in the post-translational modification of histones and regulate key cellular functions. So far only one arginine methyltransferase inhibitor discovered by random screening was available. We present the first target-based approach to protein arginine methyltransferase (PRMT) inhibitors. Homology models of human and Aspergillus nidulans PRMT1 were generated from available X-ray structures of rat PRMTs. The NCI diversity set was filtered by a target-based virtual screening to identify PRMT inhibitors. Employing a fungal PRMT for screening and a human enzyme for validation, we have identified seven inhibitors of PRMTs in vitro. Hit validation was achieved for two new inhibitors by antibody mediated detection of histone hypomethylation as well as Western blotting in cancer cells. Functional activity was proven by an observed block of estrogen receptor activation. Thus, valuable chemical tools and potential drug candidates could be identified.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína-Arginina N-Metiltransferases
/
Proteínas Repressoras
/
Histonas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Alemanha