Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer.
J Med Chem
; 64(18): 13918-13932, 2021 09 23.
Article
en En
| MEDLINE
| ID: mdl-34516133
ABSTRACT
Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH inhibitors (1 and 21) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fenoles
/
Alquenos
/
Inhibidores Enzimáticos
/
Neoplasias de la Mama Triple Negativas
/
Dihidroorotato Deshidrogenasa
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article