Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme.
Methods
; 71: 71-6, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25196325
ABSTRACT
NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Ubiquitinas
/
Descoberta de Drogas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article