JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Hang Zhang,Yujie Zhang,Yinping Geng,Xuanlong Zhen,Xiaodi Wang,Qiange Yin,Peng Zhang,Yuanyuan Li,Mengzhen Zhang,Yi-chao Zheng,Bing-rui Liu,Hui-min Liu,Hai-wei Xu
Gastric cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC50 = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric cancer cells. As a result, 7ae acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity in vivo. Collectively, 7ae has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric cancer.
研究领域:
肿瘤学
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药理学
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免疫学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Ye Hong,Yuting Wang,Ziyi Hao,Xingxia Zhang,Yejun Si,Guoqiang Lin,Shurong Zhang,Miao-Miao Niu,Xiaotian Yang,Yanming Zhang
Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy with a significant unmet clinical need for new therapeutic agents. Lysine-specific demethylase 1 (LSD1), a key regulator of leukemia stem cell self-renewal, has emerged as a promising epigenetic target for AML treatment. Herein, we employed an innovative multi-step integrated screening protocol, encompassing pharmacophore modeling, docking screening, molecular dynamics simulation, and biological evaluation, to identify novel LSD1 inhibitors. This comprehensive approach led to the discovery of six potent LSD1 inhibitors (we named these inhibitors LTMs 1–6), with LTM-1 exhibiting the most pronounced inhibitory effects on LSD1 (IC50 = 2.11 ± 0.14 nM) and the highest selectivity for LSD1 over LSD2 (>2370-fold). Notably, LTM-1 demonstrated outstanding antitumor activity both in vitro and in vivo. In vitro, LTM-1 showed potent anti-proliferative effects against LSD1-addicted MV-4-11 leukemia cells (IC50 = 0.16 ± 0.01 μM). In vivo, LTM-1 treatment significantly reduced tumor growth in MV-4-11 xenografted mice. Moreover, LTM-1 did not induce significant changes in liver and kidney function indices, suggesting a favorable safety profile. These results indicate that LTM-1 is a highly promising preclinical candidate for AML treatment, offering a new strategy for the development of more effective and selective LSD1 inhibitors.
研究领域:
药理学
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肿瘤学
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计算生物学
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DOI
PubMed
高影响因子
INVESTIGATIONAL NEW DRUGS
·
2023
·Vol. 41
·期 1
·134-141
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IF 3.4
Yan Gaobo,Zhang Hongyan,Li Yan,Miao Guoqiang,Liu Xiaolei,Lv Qifan
Lysine-specific demethylase 1 (LSD1) has been a promising target to treat prostate cancer, and discovery of novel LSD1 inhibitors would have great clinical significance. In this work, viscosalactone B was first identified as a novel LSD1 inhibitor. Viscosalactone B isolated from Withania Somnifera displayed antiproliferative activity against PC3, DU145, C42B, PC3/MDVR, DU145/MDVR, and C42B/MDVR cells with IC 50 values of 1.17, 0.72, 3.86, 2.06, 0.96 and 1.15 μM, respectively. In comparison, it was a selective LSD1 inhibitor with an IC 50 value of 970.27 nM and could induce a significant accumulation of LSD1 substrates H3K9me1, H3K9me2, and H3K4me1 in a concentration-dependent manner in DU145 cells. According to docking studies, it formed hydrogen bonds with the Thr11, Lys14, and Arg8 residues of LSD1. Importantly, while it displayed potent antitumor efficacy in vivo, it did not show obvious cytotoxicity on the major organs of nude mice. Therefore, viscosalactone B, as a novel LSD1 inhibitor, is a potential candidate that can be used for the treatment of prostate cancer in clinics.
研究领域:
肿瘤学
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药理学
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分子生物学
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化学生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 6.7
Hui-Min Liu,Xiao-Peng Xiong,Jiang-Wan Wu,He-Xiang Chen,Ying Zhou,Shi-Kun Ji,Xing-Jie Dai,Yi-Chao Zheng,Hong-Min Liu
LSD1 is overexpressed in various cancers and promotes tumor cell proliferation , tumor expansion, and suppresses immune cells infiltration and is closely associated with immune checkpoint inhibitors therapy. Therefore, the inhibition of LSD1 has been recognized as a promising strategy for cancer therapy. In this study, we screened an in-house small-molecule library targeting LSD1, an FDA-approved drug amsacrine for acute leukemia and malignant lymphomas was found to exhibit moderate anti-LSD1 inhibitory activity (IC 50 = 0.88 μM). Through further medicinal chemistry efforts, the most active compound 6x increased anti-LSD1 activity significantly (IC 50 = 0.073 μM). Further mechanistic studies demonstrated that compound 6x inhibited the stemness and migration of gastric cancer cell, and decreased the expression of PD-L1 (programmed cell death-ligand 1) in BGC-823 and MFC cells. More importantly, BGC-823 cells are more susceptible to T-cell killing when treated with compound 6x. Moreover, tumor growth was also suppressed by compound 6x in mice. Altogether, our findings demonstrated that acridine-based novel LSD1 inhibitor 6x may be a lead compound for the development of activating T cell immune response in gastric cancer cells.
研究领域:
肿瘤学
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免疫治疗
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药物化学
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癌症生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 7.3
Xing-Jie Dai,Li-Juan Zhao,Long-Hua Yang,Ting Guo,Lei-Peng Xue,Hong-Mei Ren,Zhi-Li Yin,Xiao-Peng Xiong,Ying Zhou,Shi-Kun Ji,Hui-Min Liu,Hong-Min Liu,Ying Liu,Yi-Chao Zheng
Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 μM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 μM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 6.7
Xing-Jie Dai,Ying Liu,Ning Wang,He-Xiang Chen,Jiang-Wan Wu,Xiao-Peng Xiong,Shi-Kun Ji,Ying Zhou,Liang Shen,Shao-Peng Wang,Hong-Min Liu,Hui-Min Liu,Yi-Chao Zheng
Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x ), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC 50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC 50 = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac . Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.
研究领域:
癌症免疫疗法
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药理学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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