Structure-based virtual screening and identification of a novel androgen receptor antagonist.
J Biol Chem
; 287(36): 30769-80, 2012 Aug 31.
Article
en En
| MEDLINE
| ID: mdl-22798067
ABSTRACT
Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4-2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
/
Modelos Moleculares
/
Receptores Androgénicos
/
Niacinamida
/
Antagonistas de Receptores Androgénicos
/
Isoquinolinas
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Biol Chem
Año:
2012
Tipo del documento:
Article