Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors.
J Med Chem
; 60(9): 4023-4035, 2017 05 11.
Article
em En
| MEDLINE
| ID: mdl-28409639
ABSTRACT
Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Morfolinas
/
Serina-Treonina Quinases TOR
/
Inibidores de Fosfoinositídeo-3 Quinase
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article