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

Bo Wang; Shu Wu Wang; Ying Zhou; Shao Peng Wang; Ya Gao; Hui Min Liu; Shi Kun Ji; Sai Qi Wang; Yi Chao Zheng; Cheng Zhang; Adil Mardinoglu; Hong Min Liu; Xiao Bing Chen; Xing Jie Dai

doi:10.1021/acs.jmedchem.4c00972

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

Bo Wang, Shu Wu Wang, Ying Zhou, Shao Peng Wang, Ya Gao, Hui Min Liu, Shi Kun Ji, Sai Qi Wang, Yi Chao Zheng, Cheng Zhang, Adil Mardinoglu, Hong Min Liu, Xiao Bing Chen^*, Xing Jie Dai^*

^*Corresponding author for this work

The Third Affiliated Hospital of Zhengzhou University

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Pages (from-to)	16165-16184
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	18
Early online date	12 Sept 2024
DOIs	https://doi.org/10.1021/acs.jmedchem.4c00972
Publication status	Published - 26 Sept 2024

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Wang, B., Wang, S. W., Zhou, Y., Wang, S. P., Gao, Y., Liu, H. M., Ji, S. K., Wang, S. Q., Zheng, Y. C., Zhang, C., Mardinoglu, A., Liu, H. M., Chen, X. B., & Dai, X. J. (2024). Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer. Journal of Medicinal Chemistry, 67(18), 16165-16184. https://doi.org/10.1021/acs.jmedchem.4c00972

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

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.",

author = "Bo Wang and Wang, {Shu Wu} and Ying Zhou and Wang, {Shao Peng} and Ya Gao and Liu, {Hui Min} and Ji, {Shi Kun} and Wang, {Sai Qi} and Zheng, {Yi Chao} and Cheng Zhang and Adil Mardinoglu and Liu, {Hong Min} and Chen, {Xiao Bing} and Dai, {Xing Jie}",

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doi = "10.1021/acs.jmedchem.4c00972",

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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

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.

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ER -

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

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