Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer.
Biochem Pharmacol
; 177: 113946, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32247852
ABSTRACT
Androgen receptor (AR) is a crucial driver of prostate cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Proteínas
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Receptores Androgênicos
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Ensaios Antitumorais Modelo de Xenoenxerto
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Difenilamina
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Antagonistas de Receptores de Andrógenos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China