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ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway.

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机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China [2]Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China [3]Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China [4]National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China

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关键词： Colorectal cancer Cervical cancer H3K4 methylation Chemotherapy sensitivity

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Lysine-specific demethylase1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the mechanism underlying the role of LSD1 in oncogenesis is poorly understood, and more effective LSD1 inhibitors are needed. Here we report the biological activity of a novel LSD1 inhibitor named ZY0511. ZY0511 specifically inhibited LSD1 activity and the proliferation of various human cancer cells especially the HeLa and HCT116 cells. ZY0511 significantly increased the expression of DDIT4, a known mTORC1 suppressor, which was a direct downstream target of LSD1 confirmed by ChIP-PCR. ZY0511-induced LSD1 inhibition upregulated the expression of DDIT4 by altering histone H3K4 methylation levels at its promoter, thus suppressing mTORC1 activity. Knockdown of DDIT4 attenuated the anticancer effect of ZY0511. Intraperitoneal administration of ZY0511 significantly prevented the growth of HCT116 and HeLa xenografts in mice and showed no detectable toxicity. Moreover, DDIT4 expression was correlated with the sensitivity of human cancer cells to chemotherapy. Taken together, ZY0511 showed therapeutic potential for solid tumors, the induction of DDIT4 may be used as a predictive biomarker of LSD1 inhibitors. Copyright © 2019 Elsevier B.V. All rights reserved.

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出版当年[2019]版：

大类 | 2 区

医学

小类 | 2 区肿瘤学

最新[2023]版：

大类 | 1 区

医学

小类 | 2 区肿瘤学

第一作者：

第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China

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通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China [*1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #17, 3rd Section, Ren min South Road, Chengdu, 610041, China. [*2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #17, 3rd Section, Ren min South Road, Chengdu, 610041, China.

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