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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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
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
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.
研究领域:
肿瘤学
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免疫学
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药物化学
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PubMed
高影响因子
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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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
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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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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2023
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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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高影响因子
INVESTIGATIONAL NEW DRUGS
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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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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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PubMed
高影响因子
LIFE SCIENCES
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2021
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IF 5.037
Nan Li,Liang Yang,Hongling Zuo
Aims Epithelial ovarian carcinoma is the most lethal female reproductive malignancy in the world. Paclitaxel and carboplatin are generally the first-line treatment drugs for ovarian cancer patients, but numerous patients may develop chemotherapy resistance. Thus, it is urgent to identify novel drugs for ovarian cancer treatment. Arborinine has been known as a broad-spectrum anti-tumor agent due to it possesses a potent cytotoxic effect on various cancer cells. Materials and methods This study aimed to evaluate its anti-tumor effect and the potential underlying mechanism on ovarian cancer cell line SKOV3. The effect of arborinine on SKOV3 cell proliferation and movement were evaluated by MTT assay and cell migration and invasion assays, respectively. The RT-qPCR and Western Blot assays were employed to determine target gene expression. The tumor-bearing mouse model was applied to assess the anti-tumor effect of arborinine in vivo. Key findings Our results demonstrated that arborinine treatment significantly inhibited the cell proliferation and tumor growth of SKOV3 in a dose-dependent manner. Arborinine treatment dose-dependently reduced LSD1 expression, resulting in increased H3K4m1 expression. Importantly, arborinine also potently suppressed cell migration and invasion of SKOV3 via reducing epithelial-mesenchymal transition (EMT) of SKOV3. Significance Arborinine may serve as a potential drug candidate for developing new strategies for ovarian cancer treatment.
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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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Xing-Jie Dai,Leipeng Xue,Ying Liu,Shu-Wu Wang,Ying Li,Jia-Yi Yin,Hao-Zhe Long,Hui-Min Liu,Ning Wang,Guo-Liang Lu,Yan Li,Hong-Min Liu,Bo Wang,Yi-Chao Zheng
Lysine-specific demethylase 1 (LSD1) is a validated cancer therapeutic target, critically implicated in maintaining cancer stem cells (CSCs) across leukemia and solid tumors. Although numerous potent LSD1 inhibitors have been developed, none have reached clinical approval, underscoring the need for novel agents with improved efficacy. Using a scaffold-hopping strategy, we designed and synthesized a novel class of phenoxazine-based LSD1 inhibitors. Among them, X-1 (IC50 = 0.082 μM) emerged as the most potent, exhibiting a 3-fold improvement in activity over the previously reported compound 3s (IC50 = 0.247 μM). Mechanistic studies revealed that X-1 suppressed the stemness of gastric cancer cells by interrupting the β-catenin-mediated transcriptional program, thereby reducing the expression of stemness-related proteins. In vivo studies confirmed its robust antitumor efficacy by inhibiting tumor proliferation and stemness without significant toxicity. Our findings identify X-1 as a promising LSD1-targeted inhibitor, offering a potential therapeutic strategy for gastric cancer.
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高影响因子
Acta Pharmaceutica Sinica B
·
2025
·Vol. 15
·期 12
·6657
·
IF 14.6
Yu Zhao,Danyang Zhang,Lin Meng,Siming Shan,Chao Zhang,Zhenzhong Deng,Chao Han,Lingyi Kong
Programmed cell death protein-1/programmed cell death ligand-1 (PD1/PD-L1) blockade has shown promise in cancer therapy but remains limited by low response rates. Recent efforts have explored strategies to enhance immunotherapy efficacy. Histone lysine-specific demethylase 1 (LSD1) inhibition can enhance tumor immune responses by downregulating PD-L1 expression. Furthermore, PD-L1 in tumor cell-derived extracellular vesicles (EVs) contributes to the immunosuppressive tumor microenvironment (TME) and promotes immune evasion. Here, we found that LSD1 inhibition can mediate the rearrangement of PD-L1 on tumor cell surfaces, reduce the secretion of EVs and PD-L1 levels in the TME, and ultimately block the long-range immunosuppression caused by tumor cell-released EVs. Therefore, we developed a TME-targeted synergistic therapy system with a dual mechanism in which anti-PD1 therapy blocks immune checkpoints, and forsythiaside A (FA) acts as an LSD1 inhibitor to regulate EVs secretion. Additionally, CD4 + T cells can directly kill tumor cells by inducing G1/S cell cycle arrest. Ultimately, this system activates the tumor immune response within the TME, effectively inhibiting the growth of non-small cell lung cancer tumors. Our work highlights the signaling role of EVs and the capacity of CD4 + T cells to arrest the cell cycle, offering a new approach to enhance response to anti-PD1/PD-L1 therapy. This study highlights the critical role of LSD1 in tumor immunotherapy, underscores the function of EVs as key signaling hubs bridging tumors and T cells, and reveals the direct contribution of CD4 + T cells to tumor clearance.
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高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2021
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IF 5.051
Lijuan Ding,Feng Wei,Nanya Wang,Yue Sun,Qiang Wang,Xia Fan,Ling Qi,Shudong Wang
A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC50 value of 0.32 μM. Compound 17a could effectively inhibit tubulin polymerisation with an IC50 value of 1.27 μM. Meanwhile, it selectively suppressed LSD1 with an IC50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Mengzhen Gu,Xiaoqing Xu,Xiaoping Wang,Yun Wang,Yu Zhao,Xiaoxian Hu,Lu Zhu,Zhenzhong Deng,Chao Han
Histone lysine-specific demethylase 1 (LSD1) is hyperactive in breast cancer, which is associated with the metastasis of the tumor. Current irreversible LSD1 inhibitors are all synthesized by covalently binding to the flavin adenine dinucleotide cofactor, which often have side effects due to the high affinity for a variety of targets. Here, we identified isoforsythiaside (IFA), a natural phenylpropanoid glycoside isolated from Forsythia suspensa, as a novel covalent inhibitor of LSD1. The target ligand fishing technique and LC–MS/MS analysis identified that IFA could covalently bind to the Ser817 residue of LSD1 by α,β-unsaturated ketone moiety to block the amine oxidase-like domain of LSD1. Moreover, RBMS3/Twist1/MMP2, the downstream signaling pathway of LSD1, was activated after IFA treatment to inhibit the metastasis of MDA-MB-231 cells in vitro and in vivo. This study provided novel molecular templates for development of LSD1 covalence-binding inhibitor and laid a foundation for developing agents against breast carcinoma metastasis for targeting LSD1.
研究领域:
癌症生物学
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药理学
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分子生物学
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生物化学
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PubMed
高影响因子
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