Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer

TY - JOUR

T1 - Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer

AU - Wang, Bo

AU - Wang, Shu Wu

AU - Zhou, Ying

AU - Wang, Shao Peng

AU - Gao, Ya

AU - Liu, Hui Min

AU - Ji, Shi Kun

AU - Wang, Sai Qi

AU - Zheng, Yi Chao

AU - Zhang, Cheng

AU - Mardinoglu, Adil

AU - Liu, Hong Min

AU - Chen, Xiao Bing

AU - Dai, Xing Jie

N1 - Publisher Copyright: © 2024 American Chemical Society.

PY - 2024/9/26

Y1 - 2024/9/26

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85204050778

U2 - 10.1021/acs.jmedchem.4c00972

DO - 10.1021/acs.jmedchem.4c00972

M3 - Article

C2 - 39264726

AN - SCOPUS:85204050778

SN - 0022-2623

VL - 67

SP - 16165

EP - 16184

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -