The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models.
Nat Commun
; 5: 5086, 2014 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-25271708
ABSTRACT
A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2-p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation. SP-141 has strong in vitro and in vivo antibreast cancer activity, with no apparent host toxicity. While further investigation is needed, our data indicate that SP-141 is a novel targeted therapeutic agent that may especially benefit patients with advanced disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Neoplasias da Mama
/
Proteínas Proto-Oncogênicas c-mdm2
/
Indóis
/
Antineoplásicos
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos