Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors.
ACS Med Chem Lett
; 9(4): 312-317, 2018 Apr 12.
Article
em En
| MEDLINE
| ID: mdl-29670692
ABSTRACT
In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Ano de publicação:
2018
Tipo de documento:
Article