Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer.
J Med Chem
; 67(18): 16165-16184, 2024 Sep 26.
Article
in En
| MEDLINE
| ID: mdl-39264726
ABSTRACT
LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed. Herein, we reported a series of novel quinazoline-based LSD1 inhibitors. Among them, compound Z-1 exhibited the best LSD1 inhibitory activity (IC50 = 0.108 µM). Z-1 also acted as a selective and cellular active as an LSD1 inhibitor. Furthermore, Z-1 promoted response of gastric cancer cells to T-cell killing effect by decreasing PD-L1 expression and further attenuated the PD-1/PD-L1 interaction. In vivo, Z-1 exhibited significant suppression effect on the growth of gastric cancer cells without obvious toxicity. Therefore, Z-1 represents a potential novel immunomodulator that targets LSD1, providing a lead compound with new function mechanism for gastric cancer treatment.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach Neoplasms
/
Histone Demethylases
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Country of publication:
Estados Unidos