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Sun F, Gao X, Wang W, Zhao X, Zhang J, Zhu Y. Predictive biomarkers in the era of immunotherapy for gastric cancer: current achievements and future perspectives. Front Immunol 2025; 16:1599908. [PMID: 40438098 PMCID: PMC12116377 DOI: 10.3389/fimmu.2025.1599908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Accepted: 04/24/2025] [Indexed: 06/01/2025] Open
Abstract
Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.
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Affiliation(s)
- Fujing Sun
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Xiaozhuo Gao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Wentao Wang
- Department of Gastric Surgery, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Xiaoyan Zhao
- Department of Gynecology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
- Graduate School, Dalian Medical University, Dalian, China
| | - Jingdong Zhang
- Department of Gastroenterology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
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Wang N, Li D, Zhang T, Pachai MR, Cho WH, Khudoynazarova MN, Schoeps DM, Bao Y, Liu M, Tang L, Yelena J, Chi P, Chen Y. Loss of Kmt2c / d promotes gastric cancer initiation and confers vulnerability to mTORC1 inhibition and anti-PD1 immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.27.645747. [PMID: 40236091 PMCID: PMC11996406 DOI: 10.1101/2025.03.27.645747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
KMT2C and KMT2D ( KMT2C/D ) are frequently mutated in gastric adenocarcinoma, yet their function in cancer initiation remains poorly understood. In this study, based on the observation that loss-of-function mutations of KMT2C and KMT2D are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models to selectively knock out Kmt2c and Kmt2d in gastric epithelial cells with Tmprss2-CreER T2 . Through histological staining and single-cell RNA sequencing, we observed that Kmt2c/d loss led to nuclear dysplasia and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks post Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human gastric adenocarcinoma. Kmt2c/d knockout reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering sensitivity to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTROC1 inhibition and anti-PD1 immunotherapy significantly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c / d loss in gastric cancer initiation and suggest the potential therapeutic strategies for KMT2C/D -deficient gastric cancer.
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Chen P, Chen Z, Sui W, Han W. Recent advances in the mechanisms of PD-L1 expression in gastric cancer: a review. Biol Res 2025; 58:16. [PMID: 40091086 PMCID: PMC11912799 DOI: 10.1186/s40659-025-00597-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 03/07/2025] [Indexed: 03/19/2025] Open
Abstract
In the progression of gastric cancer (GC), various cell types in the tumor microenvironment (TME) exhibit upregulated expression of programmed death ligand 1 (PD-L1), leading to impaired T-cell function and evasion of immune surveillance. Infection with H. pylori and EBV leads to increased PD-L1 expression in various cell types within TME, resulting in immune suppression and facilitating immune escape of GC cells. In the TME, mesenchymal stem cells (MSCs), M1-like tumor-associated macrophages (MI-like TAM), and myeloid-derived suppressor cells (MDSCs) contribute to the upregulation of PD-L1 expression in GC cells. Conversely, mast cells, M2-like tumor-associated macrophages (M2-like TAM), and tumor-associated neutrophils (TANs) exhibit elevated levels of PD-L1 expression in response to the influence of GC cells. Together, these factors collectively contribute to the upregulation of PD-L1 expression in GC. This review aims to provide a comprehensive summary of the cellular expression patterns of PD-L1 in GC and the underlying molecular mechanisms. Understanding the complex regulatory pathways governing PD-L1 expression may offer novel insights for the development of effective immunotherapeutic interventions.
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Affiliation(s)
- Peifeng Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China
| | - Zhangming Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China
| | - Wannian Sui
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China
| | - Wenxiu Han
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China.
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Wang S, Yang C, Tang J, Wang K, Cheng H, Yao S, Huang Z, Fei B. LSD1 is a targetable vulnerability in gastric cancer harboring TP53 frameshift mutations. Clin Epigenetics 2025; 17:26. [PMID: 39966827 PMCID: PMC11837680 DOI: 10.1186/s13148-025-01829-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND TP53 mutations are linked to aggressive progression and chemoresistance in gastric cancer (GC). Frameshift mutation is the second most common mutation type of TP53. However, the consequences of this mutation type in GC were not well understood, and targeted therapies for cancer patients harboring frameshift mutations were also not established. Histone methylation significantly influences tumorigenesis in TP53-mutated cancers, and related inhibitors are emerging as specific therapeutic strategies. METHODS AND RESULTS By treating GC cell lines harboring various TP53 mutation types with a library of histone demethylase inhibitors, we identified that GSK690, a reversible inhibitor of lysine-specific demethylase 1 (LSD1), selectively inhibits GC cells harboring TP53 frameshift mutations without nuclear localization sequence (NLS) (termed TP53 Frameshift NLS), which accounts for 89% TP53 frameshift mutations in GC patients. GSK690 showed significant specific inhibition in vitro and in vivo against this subtype by inducing G1/S cell cycle arrest via the LSD1-CCNA2 axis. Importantly, dual-luciferase assays and ChIP-qPCR confirmed that the loss of transcriptional repression activities of p53 in drives LSD1 upregulation in TP53 Frameshift NLS cancer cells. CONCLUSIONS In summary, our results indicate that the nuclear localization deficiency of p53 accounts for increased expression of LSD1 in TP53 Frameshift NLS GCs. GSK690 inhibits cell cycle progression and tumor growth by suppressing aberrantly activated LSD1-CCNA2 signaling in this GC subtype, counteracting malignant proliferation and thereby providing a precise therapeutic strategy for GC patients with TP53 Frameshift NLS.
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Affiliation(s)
- Suzeng Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Chunyu Yang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Junhui Tang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Kaiqing Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Hao Cheng
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Surui Yao
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Zhaohui Huang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China.
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China.
| | - Bojian Fei
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China.
- Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China.
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5
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He ZX, Gao G, Qiao H, Dong GJ, Dan Z, Li YL, Qi YR, Zhang Q, Yuan S, Liu HM, Dong J, Zhao W, Ma LY. Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling. J Med Chem 2024; 67:18699-18723. [PMID: 39158077 DOI: 10.1021/acs.jmedchem.4c00713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/20/2024]
Abstract
DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.
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Affiliation(s)
- Zhang-Xu He
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ge Gao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Hui Qiao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Guan-Jun Dong
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zengyangzong Dan
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ya-Lan Li
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yu-Ruo Qi
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Qian Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shuo Yuan
- Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jianzeng Dong
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Wen Zhao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Li-Ying Ma
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
- China Meheco Topfond Pharmaceutical Co., Zhumadian 463000, China
- Key Laboratory of Cardiocerebrovascular Drugs, Zhumadian 463000, Henan Province, China
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6
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Wang B, Wang SW, Zhou Y, Wang SP, Gao Y, Liu HM, Ji SK, Wang SQ, Zheng YC, Zhang C, Mardinoglu A, Liu HM, Chen XB, Dai XJ. Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer. J Med Chem 2024; 67:16165-16184. [PMID: 39264726 DOI: 10.1021/acs.jmedchem.4c00972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2024]
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.
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Affiliation(s)
- Bo Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shu-Wu Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ying Zhou
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shao-Peng Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Hui-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shi-Kun Ji
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Sai-Qi Wang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden
- Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome Interactions, King's College London, London WC2R 2LS, U.K
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiao-Bing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Xing-Jie Dai
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
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Li W, Wei J, Cheng M, Liu M. Unveiling promising targets in gastric cancer therapy: A comprehensive review. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200857. [PMID: 39280587 PMCID: PMC11396074 DOI: 10.1016/j.omton.2024.200857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Gastric cancer (GC) poses a significant global health challenge, ranking fifth in incidence and third in mortality among all malignancies worldwide. Its insidious onset, aggressive growth, proclivity for metastasis, and limited treatment options have contributed to its high fatality rate. Traditional approaches for GC treatment primarily involve surgery and chemotherapy. However, there is growing interest in targeted therapies and immunotherapies. This comprehensive review highlights recent advancements in GC targeted therapy and immunotherapy. It delves into the mechanisms of various strategies, underscoring their potential in GC treatment. Additionally, the review evaluates the efficacy and safety of relevant clinical trials. Despite the benefits observed in numerous advanced GC patients with targeted therapies and immunotherapies, challenges persist. We discuss pertinent strategies to overcome these challenges, thereby providing a solid foundation for enhancing the clinical effectiveness of targeted therapies and immunotherapies.
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Affiliation(s)
- Wenke Li
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Jing Wei
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Mo Cheng
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Ming Liu
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
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Yang FF, Liu JJ, Xu XL, Hu T, Liu JQ, He ZX, Zhao GY, Wei B, Ma LY. Discovery of Novel Imidazo[1,2- a]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect. J Med Chem 2024; 67:14345-14369. [PMID: 39102466 DOI: 10.1021/acs.jmedchem.4c01168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2024]
Abstract
Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.
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Affiliation(s)
- Fei-Fei Yang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
- School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou 450046, China
| | - Jing-Jing Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Xue-Li Xu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Ting Hu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Jian-Quan Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Zhang-Xu He
- School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou 450046, China
| | - Guang-Yuan Zhao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Bo Wei
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Li-Ying Ma
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China
- China Meheco Topfond Pharmaceutical Co.; Key Laboratory of Cardio-cerebrovascular Drug, Zhumadian 463000, China
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9
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Li A, Ma T, Wang S, Guo Y, Song Q, Liu H, Yu B, Feng S. Discovery of WS-384, a first-in-class dual LSD1 and DCN1-UBC12 protein-protein interaction inhibitor for the treatment of non-small cell lung cancer. Biomed Pharmacother 2024; 173:116240. [PMID: 38401512 DOI: 10.1016/j.biopha.2024.116240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/26/2024] Open
Abstract
Abnormally high expression of lysine-specific demethylase 1 A (LSD1) and DCN1 plays a vital role in the occurrence, development, and poor prognosis of non-small cell lung cancer (NSCLC). Accumulating evidence has shown that the development of small-molecule inhibitors dually targeting LSD1 and the DCN1-UBC12 interaction probably have therapeutic promise for cancer therapy. This work reported that WS-384 dually targeted LSD1 and DCN1-UBC12 interactions and evaluated its antitumor effects in vitro and in vivo. Specifically, WS-384 inhibited A549 and H1975 cells viability and decreased colony formation and EdU incorporation. WS-384 could also trigger cell cycle arrest, DNA damage, and apoptosis. Moreover, WS-384 significantly decreased tumor weight and volume in A549 xenograft mice. Mechanistically, WS-384 increased the gene and protein level of p21 by suppressing the neddylation of cullin 1 and decreasing H3K4 demethylation at the CDKN1A promoter. The synergetic upregulation of p21 contributed to cell cycle arrest and the proapoptotic effect of WS-384 in NSCLC cells. Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.
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Affiliation(s)
- Anqi Li
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Ting Ma
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Shuai Wang
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Yueyang Guo
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Qianqian Song
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Hongmin Liu
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
| | - Bin Yu
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
| | - Siqi Feng
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
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10
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Han D, Lu J, Fan B, Lu W, Xue Y, Wang M, Liu T, Cui S, Gao Q, Duan Y, Xu Y. Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies. Molecules 2024; 29:550. [PMID: 38276629 PMCID: PMC10821146 DOI: 10.3390/molecules29020550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/31/2023] [Accepted: 01/08/2024] [Indexed: 01/27/2024] Open
Abstract
Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.
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Affiliation(s)
- Di Han
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Jiarui Lu
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Baoyi Fan
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Wenfeng Lu
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Yiwei Xue
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Meiting Wang
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Taigang Liu
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
| | - Shaoli Cui
- School of Forensic, Xinxiang Medical University, Xinxiang 453003, China
| | - Qinghe Gao
- School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
| | - Yingchao Duan
- School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
| | - Yongtao Xu
- School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; (D.H.); (J.L.)
- Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang 453003, China
- Xinxiang Key Laboratory of Biomedical Information Research, Xinxiang 453003, China
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11
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Moreno-Perea M, Suárez-Castro A, Fraire-Soto I, Sifuentes-Padilla JL, Gutiérrez-Hernández R, Reyes-Estrada CA, López-Hernández Y, Cortés-García CJ, Chacón-García L, Granados-López AJ, López JA. Proliferation, Migration and Invasion of Breast Cancer Cell Lines Are Inhibited by 1,5-Disubstituted Tetrazol-1,2,3-triazole Hybrids through Interaction with p53. Molecules 2023; 28:7600. [PMID: 38005322 PMCID: PMC10673467 DOI: 10.3390/molecules28227600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/19/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
The anticarcinogenic potential of a series of 1,5-disubstituted tetrazole-1,2,3-triazole hybrids (T-THs) was evaluated in the breast cancer (BC)-derived cell lines MCF-7 (ER+, PR+, and HER2-), CAMA-1 (ER+, PR+/-, and HER2-), SKBR-3 (ER+, PR+, and HER2+), and HCC1954 (ER+, PR+, and HER2+). The T-THs 7f, 7l, and 7g inhibited the proliferation of MCF-7 and CAMA-1, HCC1954, and SKBR-3 cells, respectively. The compounds with stronger effect in terms of migration and invasion inhibition were 7o, 7b, 7n, and 7k for the CAMA-1, MCF-7, HCC1954, and SKBR-3 cells respectively. Interestingly, these T-THs were the compounds with a fluorine present in their structures. To discover a possible target protein, a molecular docking analysis was performed for p53, p38, p58, and JNK1. The T-THs presented a higher affinity for p53, followed by JNK1, p58, and lastly p38. The best-predicted affinity for p53 showed interactions between the T-THs and both the DNA fragment and the protein. These results provide an opportunity for these compounds to be studied as potential drug candidates for breast cancer treatment.
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Affiliation(s)
- Marisol Moreno-Perea
- Laboratorio de microRNAs y Cáncer, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Agronómica, Campus II, Zacatecas 98066, Zacatecas, Mexico
| | - Abel Suárez-Castro
- Laboratorio de Diseño Molecular, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Ciudad Universitaria, Morelia 58033, Michoacán, Mexico
| | - Ixamail Fraire-Soto
- Laboratorio de microRNAs y Cáncer, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Agronómica, Campus II, Zacatecas 98066, Zacatecas, Mexico
| | - Jessica Lizbeth Sifuentes-Padilla
- Laboratorio de microRNAs y Cáncer, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Agronómica, Campus II, Zacatecas 98066, Zacatecas, Mexico
| | - Rosalinda Gutiérrez-Hernández
- Unidad Académica de Enfermería, Universidad Autónoma de Zacatecas, Campus Siglo XXI, Edificio L-1, Segundo Piso, Carretera Zacatecas-Guadalajara Km 6, Ejido La Escondida, Zacatecas 98160, Zacatecas, Mexico
| | - Claudia Araceli Reyes-Estrada
- Maestría en Ciencias de la Salud con Especialidad en Salud Pública, Unidad Academica de Medicina Human, UAZ, Campus Siglo XXI, Edificio L-1, Segundo Piso, Carretera Zacatecas-Guadalajara Km 6, Ejido La Escondida, Zacatecas 98160, Zacatecas, Mexico
| | - Yamilé López-Hernández
- Laboratorio de Metabolómica y Proteómica, Cátedra CONACYT, Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Agronómica, Campus II, Zacatecas 98066, Zacatecas, Mexico
| | - Carlos J Cortés-García
- Laboratorio de Diseño Molecular, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Ciudad Universitaria, Morelia 58033, Michoacán, Mexico
| | - Luis Chacón-García
- Laboratorio de Diseño Molecular, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Ciudad Universitaria, Morelia 58033, Michoacán, Mexico
| | - Angelica Judith Granados-López
- Laboratorio de microRNAs y Cáncer, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Agronómica, Campus II, Zacatecas 98066, Zacatecas, Mexico
| | - Jesús Adrián López
- Laboratorio de microRNAs y Cáncer, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Agronómica, Campus II, Zacatecas 98066, Zacatecas, Mexico
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12
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Dai XJ, Liu Y, Wang N, Chen HX, Wu JW, Xiong XP, Ji SK, Zhou Y, Shen L, Wang SP, Liu HM, Liu HM, Zheng YC. Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer. Eur J Med Chem 2023; 259:115684. [PMID: 37542989 DOI: 10.1016/j.ejmech.2023.115684] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/27/2023] [Accepted: 07/24/2023] [Indexed: 08/07/2023]
Abstract
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 IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 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.
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Affiliation(s)
- Xing-Jie Dai
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Ying Liu
- Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, China
| | - Ning Wang
- The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - He-Xiang Chen
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Jiang-Wan Wu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Xiao-Peng Xiong
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Shi-Kun Ji
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Ying Zhou
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Liang Shen
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Shao-Peng Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Hong-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China
| | - Hui-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China.
| | - Yi-Chao Zheng
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China.
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13
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Tang J, Liu J, He X, Fu S, Wang K, Li C, Li Y, Zhu Y, Gong P, Zhao Y, Liu Y, Hou Y. Design and Synthesis of 1,3,5-Triazines or Pyrimidines Containing Dithiocarbamate Moiety as PI3Kα Selective Inhibitors. ACS Med Chem Lett 2023; 14:1266-1274. [PMID: 37736169 PMCID: PMC10510507 DOI: 10.1021/acsmedchemlett.3c00287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 08/03/2023] [Indexed: 09/23/2023] Open
Abstract
Recent studies have shown that phosphoinositide 3-kinase (PI3K) plays a vital role in cell division, and it has become a therapeutic target for many cancers. In this paper, some new 1,3,5-triazine or pyrimidine skeleton derivatives containing dithiocarbamate were designed and synthesized based on the reasonable drug design strategy from the previously effective compound 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK-474), in order to get effective selective PI3Kα inhibitors that have not been reported in the literature. In addition, the inhibitory activities of these compounds on PI3Kα and two tumor cell lines in vitro (HCT-116, U87-MG) were evaluated. The representative compound 13 showed a half-maximal inhibitory concentration (IC50) value of 1.2 nM for PI3Kα and an exciting kinase selectivity. Compound 13 displayed strong efficacy in HCT-116 and U87-MG cell lines with IC50 values of 0.83 and 1.25 μM, respectively. In addition, compound 13 induced obvious tumor regression in the U87-MG cell line xenografts mouse model, with no obvious signs of toxicity after intraperitoneal injection at a dose of 40 mg/kg. Compound 13 can be an effective selective inhibitor of PI3Kα, and it provides patients with an opportunity to avoid the side effects related to the wider inhibition of the class I PI3K family.
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Affiliation(s)
| | | | - Xinzi He
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Siyu Fu
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Kang Wang
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Chunting Li
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yuan Li
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yanli Zhu
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Ping Gong
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yanfang Zhao
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yajing Liu
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yunlei Hou
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
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14
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Dai XJ, Zhao LJ, Yang LH, Guo T, Xue LP, Ren HM, Yin ZL, Xiong XP, Zhou Y, Ji SK, Liu HM, Liu HM, Liu Y, Zheng YC. Phenothiazine-Based LSD1 Inhibitor Promotes T-Cell Killing Response of Gastric Cancer Cells. J Med Chem 2023; 66:3896-3916. [PMID: 36856685 DOI: 10.1021/acs.jmedchem.2c01593] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
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.
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Affiliation(s)
- Xing-Jie Dai
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Li-Juan Zhao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Long-Hua Yang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Ting Guo
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Lei-Peng Xue
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Hong-Mei Ren
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Zhi-Li Yin
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Xiao-Peng Xiong
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Ying Zhou
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Shi-Kun Ji
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Hui-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Hong-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Ying Liu
- Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Yi-Chao Zheng
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
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15
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Al bustanji D, Alnabulsi S, Al-Hurani EA. Hit-to-lead optimization of amino-carboxamide benzothiazoles as LSD1 inhibitors. Med Chem Res 2023. [DOI: 10.1007/s00044-023-03046-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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16
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Yuan XY, Song CH, Liu XJ, Wang X, Jia MQ, Wang W, Liu WB, Fu XJ, Jin CY, Song J, Zhang SY. Discovery of novel N-benzylarylamide-dithiocarbamate based derivatives as dual inhibitors of tubulin polymerization and LSD1 that inhibit gastric cancers. Eur J Med Chem 2023; 252:115281. [PMID: 36940611 DOI: 10.1016/j.ejmech.2023.115281] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 03/08/2023] [Accepted: 03/12/2023] [Indexed: 03/17/2023]
Abstract
In this work, N-benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC50 = 0.017 μM), HCT-116 (IC50 = 0.044 μM) and KYSE450 (IC50 = 0.030 μM), but also exhibited low nanomolar IC50 values from 0.019 to 0.253 μM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of β-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N-benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers.
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Affiliation(s)
- Xin-Ying Yuan
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Chun-Hong Song
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Xiu-Juan Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Xiao Wang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Mei-Qi Jia
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wang Wang
- Luoyang Key Laboratory of Organic Functional Molecules, College of Food and Drug, Luoyang Normal University, Luoyang, 471934, China
| | - Wen-Bo Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Xiang-Jing Fu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Cheng-Yun Jin
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
| | - Jian Song
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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17
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Zhao S, Liu J, Lv Z, Zhang G, Xu Z. Recent updates on 1,2,3-triazole-containing hybrids with in vivo therapeutic potential against cancers: A mini-review. Eur J Med Chem 2023; 251:115254. [PMID: 36893627 DOI: 10.1016/j.ejmech.2023.115254] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/01/2023] [Accepted: 03/04/2023] [Indexed: 03/08/2023]
Abstract
1,2,3-Triazole moiety which is usually constructed by highly versatile, efficacious and selective copper-catalyzed azide-alkyne cycloaddition not only can act as a linker to connect different pharmacophores, but also is a useful pharmacophore with diverse biological properties. 1,2,3-Triazoles are readily interact with diverse enzymes and receptors in cancer cells through non-covalent interactions and can inhibit cancer cell proliferation, arrest cell cycle and induce apoptosis. In particular, 1,2,3-triazole-containing hybrids have the potential to exert dual or multiple anticancer mechanisms of action, representing useful scaffolds in expediting development of novel anticancer agents. The current review summarizes the in vivo anticancer efficacy and mechanisms of action of 1,2,3-triazole-containing hybrids reported in the last decade to continuously open up a map for the remarkable exploration of more effective candidates.
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Affiliation(s)
- Shijia Zhao
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, PR China
| | - Jie Liu
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, PR China
| | - Zaosheng Lv
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, PR China
| | - Guangde Zhang
- Engineering Training Center, Wuhan University of Science and Technology, Wuhan, PR China.
| | - Zhi Xu
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, PR China.
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18
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Li Z, Yuan Y, Wang P, Zhang Z, Ma H, Sun Y, Zhang X, Li X, Qiao Y, Zhang F, Su Y, Song J, Xie Z, Li L, Ma L, Ma J, Zhang Z. Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors. Eur J Med Chem 2023; 253:115321. [PMID: 37037137 DOI: 10.1016/j.ejmech.2023.115321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/26/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.
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19
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Ma QS, Zhang YF, Li CY, Zhang WX, Yuan L, Niu JB, Song J, Zhang SY, Liu HM. Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment. Eur J Med Chem 2023; 251:115228. [PMID: 36881982 DOI: 10.1016/j.ejmech.2023.115228] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/20/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023]
Abstract
As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC50 values of 14.3, 22.8 and 16.3 μM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer.
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Affiliation(s)
- Qi-Sheng Ma
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Yi-Fan Zhang
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | | | - Wei-Xin Zhang
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Lu Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jin-Bo Niu
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jian Song
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
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20
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Noce B, Di Bello E, Fioravanti R, Mai A. LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. Front Pharmacol 2023; 14:1120911. [PMID: 36817147 PMCID: PMC9932783 DOI: 10.3389/fphar.2023.1120911] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 01/20/2023] [Indexed: 02/05/2023] Open
Abstract
Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD as the cofactor. It is ubiquitously overexpressed in many types of cancers (breast, gastric, prostate, hepatocellular, and esophageal cancer, acute myeloid leukemia, and others) leading to block of differentiation and increase of proliferation, migration and invasiveness at cellular level. LSD1 inhibitors can be grouped in covalent and non-covalent agents. Each group includes some hybrid compounds, able to inhibit LSD1 in addition to other target(s) at the same time (dual or multitargeting compounds). To date, 9 LSD1 inhibitors have entered clinical trials, for hematological and/or solid cancers. Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents.
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Affiliation(s)
- Beatrice Noce
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy
| | - Elisabetta Di Bello
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy
| | - Rossella Fioravanti
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy,*Correspondence: Rossella Fioravanti,
| | - Antonello Mai
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy,Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
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21
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Mao F, Shi YG. Targeting the LSD1/KDM1 Family of Lysine Demethylases in Cancer and Other Human Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1433:15-49. [PMID: 37751134 DOI: 10.1007/978-3-031-38176-8_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Lysine-specific demethylase 1 (LSD1) was the first histone demethylase discovered and the founding member of the flavin-dependent lysine demethylase family (KDM1). The human KDM1 family includes KDM1A and KDM1B, which primarily catalyze demethylation of histone H3K4me1/2. The KDM1 family is involved in epigenetic gene regulation and plays important roles in various biological and disease pathogenesis processes, including cell differentiation, embryonic development, hormone signaling, and carcinogenesis. Malfunction of many epigenetic regulators results in complex human diseases, including cancers. Regulators such as KDM1 have become potential therapeutic targets because of the reversibility of epigenetic control of genome function. Indeed, several classes of KDM1-selective small molecule inhibitors have been developed, some of which are currently in clinical trials to treat various cancers. In this chapter, we review the discovery, biochemical, and molecular mechanisms, atomic structure, genetics, biology, and pathology of the KDM1 family of lysine demethylases. Focusing on cancer, we also provide a comprehensive summary of recently developed KDM1 inhibitors and related preclinical and clinical studies to provide a better understanding of the mechanisms of action and applications of these KDM1-specific inhibitors in therapeutic treatment.
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Affiliation(s)
- Fei Mao
- Longevity and Aging Institute (LAI), IBS and Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yujiang Geno Shi
- Longevity and Aging Institute (LAI), IBS and Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China.
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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22
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Tian MR, Du K, Zhi YL, Xue GM, Zhao ZZ, Si YY, Chen H, Sun YJ, Feng WS, Ma JL. LSD1 inhibitors from the roots of Pueraria lobata. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2023; 25:44-52. [PMID: 35113741 DOI: 10.1080/10286020.2022.2032677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/13/2022] [Accepted: 01/19/2022] [Indexed: 06/14/2023]
Abstract
One new 6a,11a-dehydropterocarpan derivative, 6-O-methyl-anhydrotuberosin (1), one new 6a-hydroxypterocarpan, (6aR,11aR,11bR)-hydroxytuberosone (7), and seven known compounds including two 6a,11a-dehydropterocarpans (2 and 4), two coumestans (3 and 5), one isoflavonoid (6) and two other phenolic compounds (8 and 9) were isolated from the roots of Pueraria lobata. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1 D and 2DNMR, HRESIMS). Compounds 1, 2, 4-5 showed potent LSD1 inhibitory activities with IC50 values ranging from 1.73 to 4.99 μM. Furthermore, compound 2 showed potent cytotoxicity against gastric cancer cell lines MGC-803 and BGC-823, and lung cancer cell lines H1299 and H460.
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Affiliation(s)
- Meng-Ru Tian
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Kun Du
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Yan-Le Zhi
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Gui-Min Xue
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Zhen-Zhu Zhao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying-Ying Si
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Hui Chen
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yan-Jun Sun
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Wei-Sheng Feng
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Jin-Lian Ma
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China
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23
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Alabed SJ, Zihlif M, Taha M. Discovery of new potent lysine specific histone demythelase-1 inhibitors (LSD-1) using structure based and ligand based molecular modelling and machine learning. RSC Adv 2022; 12:35873-35895. [PMID: 36545090 PMCID: PMC9751883 DOI: 10.1039/d2ra05102h] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Lysine-specific histone demethylase 1 (LSD-1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 and is highly overexpressed in different types of cancer. Therefore, it has been widely recognized as a promising therapeutic target for cancer therapy. Towards this end, we employed various Computer Aided Drug Design (CADD) approaches including pharmacophore modelling and machine learning. Pharmacophores generated by structure-based (SB) (either crystallographic-based or docking-based) and ligand-based (LB) (either supervised or unsupervised) modelling methods were allowed to compete within the context of genetic algorithm/machine learning and were assessed by Shapley additive explanation values (SHAP) to end up with three successful pharmacophores that were used to screen the National Cancer Institute (NCI) database. Seventy-five NCI hits were tested for their LSD-1 inhibitory properties against neuroblastoma SH-SY5Y cells, pancreatic carcinoma Panc-1 cells, glioblastoma U-87 MG cells and in vitro enzymatic assay, culminating in 3 nanomolar LSD-1 inhibitors of novel chemotypes.
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Affiliation(s)
- Shada J Alabed
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan Amman Jordan
| | - Malek Zihlif
- Department of Pharmacology, Faculty of Medicine, University of Jordan Amman Jordan
| | - Mutasem Taha
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan Amman Jordan
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24
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He X, Zhang B, Cao P, Wang H, Wu S, Wang G, Yang F, Leng A, Liang G, Li D. Biotransformation of dihydrocapsaicin by human intestinal fungi and the inhibitory effects of metabolites against LSD1. Heliyon 2022; 8:e12325. [PMID: 36578383 PMCID: PMC9791335 DOI: 10.1016/j.heliyon.2022.e12325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/22/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Dihydrocapsaicin is the main bioactive component in Capsicum plants, which is widely used in China and India as a food drug and additive. In this study, the biotransformation of dihydrocapsaicin was performed using four cultivated human intestinal fungal strains in vitro. Eight metabolites, including seven previously undescribed metabolites (1 and 3-8) and one known analog (2), were obtained. Numerous spectroscopic data, such as NMR and HRESIMS, were collected to determine their structures. Based on the structures of the dihydrocapsaicin metabolites, the main biotransformation reactions were revealed to be hydroxylation, alcohol oxidation, and lactylation. In particular, the lactylation of hydroxyl groups is mainly mediated by Rhizopus oryzae R2701. In addition, metabolite 1 showed significant inhibitory effect on lysine-specific demethylase 1 (LSD1) (IC50 1.99 μM). Therefore, the biotransformation of dihydrocapsaicin by intestinal fungi afforded various derivatives, which were important resources for developing LSD1 inhibitors and potential application in cancer treatment.
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Affiliation(s)
- Xin He
- The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China,College of Pharmacy, Dalian Medical University, Dalian 116044, China,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Baojing Zhang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Peng Cao
- General Hospital of Northern Theater Command (General Hospital of Shenyang Military Command), Department of Neurosurgery, Shenyang 110016, China
| | - Honglei Wang
- The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China,College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Shan Wu
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Gang Wang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Fangyu Yang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China,General Hospital of Northern Theater Command (General Hospital of Shenyang Military Command), Department of Neurosurgery, Shenyang 110016, China
| | - Aijing Leng
- The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Guobiao Liang
- General Hospital of Northern Theater Command (General Hospital of Shenyang Military Command), Department of Neurosurgery, Shenyang 110016, China,Corresponding author.
| | - Dawei Li
- The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China,Corresponding author.
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25
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Novel Phthalazin-1(2H)-One Derivatives Displaying a Dithiocarbamate Moiety as Potential Anticancer Agents. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238115. [PMID: 36500208 PMCID: PMC9738785 DOI: 10.3390/molecules27238115] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022]
Abstract
Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6-8, which display the dithiocarbamate scaffold at N2, and compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6-8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a-b, 9d, and 9g with IC50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.
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26
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Li B, Zhang X, Li J. Carrier-free supramolecular nanoassemblies of pure LSD1 inhibitor for effective anti-tumor therapy. Front Chem 2022; 10:1012882. [PMID: 36247676 PMCID: PMC9561089 DOI: 10.3389/fchem.2022.1012882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/14/2022] [Indexed: 12/03/2022] Open
Abstract
The LSD1 protein is an oxidase that regulates protein methylation, which regulates gene expression and triggers tumors. Previously, inhibiting LSD1 has been found to be an effective treatment strategy for opposing tumors caused by overexpression of LSD1. Our recent study found that compound 17i was a suitable LSD1 inhibitor with potential anti-tumor activity. However, its extremely insoluble nature limits further validation of its anti-tumor activity at the clinical level. In this study, a unique carrier-free supramolecular nanoassemblies of pure compound 17i is expected to enhance therapeutic efficacy. Aqueous-insoluble compound 17i was mixed with a small quantity of DSPE-PEG2000 into an organic solvent and was prepared as nanoassemblies in water via the one-step nanoprecipitation method. The 17i nanoassemblies have a similar effect on its cytotoxicity when compared with 17i solution in vitro. Importantly, the PEGylated 17i nanoassemblies exhibit significant superiorities over 17i solutions in therapeutic efficiency, anti-tumor immune response and systemic toxicity in BALB/c mice bearing CT-26 colorectal tumors. We envision that the fabrication of pure drug nanoassemblies offers an efficient platform for reforming the undesirable characteristics of drug-like compounds to potentiate the anti-tumor therapeutic effect.
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Affiliation(s)
- Boao Li
- Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang, China
| | - Xiangyu Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- *Correspondence: Xiangyu Zhang, ; Jibin Li,
| | - Jibin Li
- Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang, China
- *Correspondence: Xiangyu Zhang, ; Jibin Li,
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27
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Yang FF, Zhou JZ, Xu XL, Hu T, Liu JQ, Wu YX, Wei B, Ma LY. Discovery of 1,3,4-oxadiazole derivatives containing a bisamide moiety as a novel class of potential cardioprotective agents. Eur J Med Chem 2022; 239:114526. [PMID: 35716515 DOI: 10.1016/j.ejmech.2022.114526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/28/2022] [Accepted: 06/06/2022] [Indexed: 11/26/2022]
Abstract
Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.
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Affiliation(s)
- Fei-Fei Yang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Jin-Zhu Zhou
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Xue-Li Xu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Ting Hu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Jian-Quan Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Ya-Xi Wu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Bo Wei
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
| | - Li-Ying Ma
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, PR China; China Meheco Topfond Pharmaceutical Co., Zhumadian, 463000, PR China.
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Zhang X, Sun Y, Huang H, Wang X, Wu T, Yin W, Li X, Wang L, Gu Y, Zhao D, Cheng M. Identification of novel indole derivatives as highly potent and efficacious LSD1 inhibitors. Eur J Med Chem 2022; 239:114523. [PMID: 35732082 DOI: 10.1016/j.ejmech.2022.114523] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/04/2022] [Accepted: 06/05/2022] [Indexed: 11/04/2022]
Abstract
Lysine-specific demethylase 1 (LSD1) is a FAD-dependent histone demethylase to catalyze the demethylation of H3K4 and H3K9 and thus is an attractive target for therapeutic cancer. Starting with a high micromolar compound 17i, structure-based optimization of novel indole derivatives is described by a bioelectronic isosteric strategy. Grounded by molecular modeling, medicinal chemistry has efficiently yielded low nanomolar LSD1 inhibitors. One of the compounds, B35, exhibited excellent LSD1 inhibition (IC50 = 0.050 ± 0.005 μM) and anti-proliferation against A549 cells (IC50 = 0.74 ± 0.14 μM). The further PK studies indicated compound B35 possessed favorable metabolic stability, in which the plasma t1/2 of p.o. and i.v. were 6.27 ± 0.72 h and 8.78 ± 1.31 h, respectively. Additionally, inhibitor B35 shows a strong antitumor effect and good safety in vivo. Meanwhile, compound B35 regulated genes are closely associated with transcriptional dislocation in cancer and PI3K/AKT pathway involving IGFBP3. Taken together, B35 could be a potent LSD1 inhibitor for further drug development.
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Affiliation(s)
- Xiangyu Zhang
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yixiang Sun
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China
| | - Hailan Huang
- Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, China
| | - Xinran Wang
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Chaoyang District, Beijing, 102488, China
| | - Tianxiao Wu
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China
| | - Wenbo Yin
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China
| | - Xiaojia Li
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China
| | - Lin Wang
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China
| | - Yanting Gu
- Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, China.
| | - Dongmei Zhao
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China.
| | - Maosheng Cheng
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China
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Development of S-aryl dithiocarbamate derived novel antiproliferative compound exhibiting tubulin bundling. Bioorg Med Chem 2022; 68:116874. [PMID: 35716589 DOI: 10.1016/j.bmc.2022.116874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 05/31/2022] [Indexed: 11/23/2022]
Abstract
Cancer is a leading cause of human death, and there is a need to identify efficient and novel chemical scaffolds which could provide flexibility to cancer chemotherapeutics. This work introduces S-aryl dithiocarbamates belonging to a versatile group of organo-sulfur containing compounds as a hitherto unexplored class of effective anticancer drugs with promising pharmacophore properties. We synthesized a series of N-Boc piperazine containing S-aryl dithiocarbamates and identified compound 1 as a potent antiproliferative agent in lung, cervical, and breast cancer cell lines. Compound 1 exhibited best inhibitory activity against cervical cancer cells, HeLa with an IC50 of 0.432 ± 0.138 μM for 72 h, and lung cancer cells, A549 with an IC50 of 0.447 ± 0.051 μM for 72 h. We further demonstrate that HeLa cells treated with this compound result in G2/M phase cell cycle arrest, causing cell apoptosis due to the upregulation of the p53-p21 signaling pathway. Importantly, cells treated with compound 1 showed a novel tubulin bundling phenotype in fluorescence microscopy, which is a characteristic of microtubule-stabilizing anticancer drugs like paclitaxel. Interestingly, molecular docking analysis revealed reasonable binding of compound 1 in the taxol-binding pocket of β-tubulin, making it a promising candidate for microtubule stabilization based anticancer drug discovery.
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Lv S, Zhao X, Zhang E, Yan Y, Ma X, Li N, Zou Q, Sun L, Song T. Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma. J Biol Chem 2022; 298:102374. [PMID: 35970393 PMCID: PMC9478407 DOI: 10.1016/j.jbc.2022.102374] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/26/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) has a dismal prognosis. KDM1A, overexpressed in multiple cancer types, is a lysine demethylase that targets both histone and non-histone proteins. However, it is unclear how KDM1A expression affects HCC etiology. Here, we show KDM1A can interact with and demethylate FKBP8, a cytoplasmic protein which regulates cell survival through the anti-apoptotic protein BCL2. We show demethylation of FKBP8 enhances its ability to stabilize BCL2. Consistently, we observed positive correlation between KDM1A and BCL2 protein levels in liver cancer patients. Functionally, we reveal FKBP8 demethylation by KDM1A is critical for liver cancer cell growth in vitro and in vivo. We went on to explore the mechanisms that might regulate KDM1A cytoplasmic localization. We found the cytoplasmic localization and protein stability of KDM1A was promoted by acetylation at Lysine-117 by the acetyl transferase KAT8. In agreement with this, we show KDM1A-K117 acetylation promotes demethylation of FKBP8 and level of BCL2. Finally, it has been shown that the efficacy of Sorafenib, a first-line treatment for advanced hepatocellular carcinoma, is limited by clinical resistance. We show KDM1A and BCL2 protein levels are increased during acquired sorafenib-resistance, while inhibiting KDM1A can antagonize sorafenib-resistance. Collectively, these results define a functional KDM1A-FKBP8-BCL2 axis in hepatocellular carcinoma.
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Affiliation(s)
- Suli Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030
| | - Xuefeng Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yingying Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030
| | - Xianyun Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030
| | - Neng Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030
| | - Qingli Zou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030
| | - Lidong Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
| | - Tanjing Song
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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Alsehli M, Aljuhani A, Ihmaid SK, El-Messery SM, Othman DIA, El-Sayed AAAA, Ahmed HEA, Rezki N, Aouad MR. Design and Synthesis of Benzene Homologues Tethered with 1,2,4-Triazole and 1,3,4-Thiadiazole Motifs Revealing Dual MCF-7/HepG2 Cytotoxic Activity with Prominent Selectivity via Histone Demethylase LSD1 Inhibitory Effect. Int J Mol Sci 2022; 23:ijms23158796. [PMID: 35955929 PMCID: PMC9369007 DOI: 10.3390/ijms23158796] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/30/2022] [Accepted: 08/01/2022] [Indexed: 12/14/2022] Open
Abstract
In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure–activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04–1.5 μM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 μM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity.
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Affiliation(s)
- Mosa Alsehli
- Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia
| | - Ateyatallah Aljuhani
- Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia
| | - Saleh K. Ihmaid
- Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 42353, Saudi Arabia
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Jadara University, Irbid 21110, Jordan
| | - Shahenda M. El-Messery
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Dina I. A. Othman
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Abdel-Aziz A. A. El-Sayed
- Biology Department, Faculty of Science, Islamic University of Madinah, Al-Madinah Al-Munawarah 42351, Saudi Arabia
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Hany E. A. Ahmed
- Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 42353, Saudi Arabia
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 35511, Egypt
- Correspondence: (H.E.A.A.); (N.R.)
| | - Nadjet Rezki
- Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia
- Correspondence: (H.E.A.A.); (N.R.)
| | - Mohamed R. Aouad
- Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia
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Lv YX, Tian S, Zhang ZD, Feng T, Li HQ. LSD1 inhibitors for anticancer therapy: a patent review (2017-present). Expert Opin Ther Pat 2022; 32:1027-1042. [PMID: 35914778 DOI: 10.1080/13543776.2022.2109332] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Lysine-specific demethylase 1 (LSD1), which belongs to the demethylase of non-histone proteins, is believed to promote cancer cell proliferation and metastasis by modifying histones. LSD1 dysfunction may play a key role in a variety of cancers, such as acute myeloid leukemia and non-small cell lung cancer, indicating that LSD1 is a promising epigenetic target for cancer therapy. Many different types of small molecule LSD1 inhibitors have been developed and shown to inhibit tumor cell proliferation, invasion, and migration, providing a new treatment strategy for solid tumors. AREAS COVERED This review summarizes the progress of LSD1 inhibitor research in the last four years, including selected new patents and article publications, as well as the therapeutic potential of these compounds. EXPERT OPINION Natural products offer a promising prospect for developing novel potent LSD1 inhibitors, as structural design and activity of irreversible and reversible inhibitors have been continuously optimized since the discovery of the LSD1 target in 2004. The use of "microtubule-binding agents" and "dual-agent combination" has recently become a new anticancer technique, reducing the resistance and adverse reactions of traditional drugs. Several microtubule-binding drugs have been used successfully in clinical practice, providing structural scaffolds and new ideas for the development of safer drugs.
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Affiliation(s)
- Yi-Xin Lv
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China
| | - Sheng Tian
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China
| | - Zhou-Dong Zhang
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China
| | - Tao Feng
- Clinical Laboratory, The Children's Hospital of Suzhou University, 92 Zhongnan Street, Suzhou, Jiangsu 215025, P.R. China
| | - Huan-Qiu Li
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China
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Qin TT, Li ZH, Li LX, Du K, Yang JG, Zhang ZQ, Wu XX, Ma JL. Sanguinarine, identified as a natural alkaloid LSD1 inhibitor, suppresses lung cancer cell growth and migration. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:781-788. [PMID: 35949313 PMCID: PMC9320206 DOI: 10.22038/ijbms.2022.62541.13851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 05/28/2022] [Indexed: 11/21/2022]
Abstract
Objectives Lysine-specific demethylase1 (LSD1), an important class of histone demethylases, plays a crucial role in regulation of mammalian biology. The up-regulated LSD1 expression was frequently associated with progress and oncogenesis of multiple human cancers, including non-small cell lung cancer (NSCLC). Therefore, inhibition of LSD1 may provide an attractive strategy for cancer treatment. We investigated the effect of sanguinarine against lung cancer cells as a natural alkaloid LSD1 inhibitor. Materials and Methods The inhibition properties of sanguinarine to the recombinant LSD1 were evaluated by a fluorescence-based method. Subsequently, assays such as viability, apoptosis, clonogenicity, wound healing, and transwell were performed on H1299 and H1975 cells after treatment with sanguinarine. Results Upon screening our in-house natural chemical library toward LSD1, we found that sanguinarine possessed a potent inhibitory effect against LSD1 with the IC50 value of 0.4 μM in a reversible manner. Molecular docking simulation suggested that sanguinarine may inactivate LSD1 by inserting into the binding pocket of LSD1 to compete with the FAD site. In H1299 and H1975 cells, sanguinarine inhibited the demethylation of LSD1, validating its cellular activity against the enzyme. Further studies showed that sanguinarine exhibited a strong capacity to suppress colony formation, inhibit migration and invasion, as well as induce apoptosis of H1299 and H1975 cells. Conclusion Our findings present a new chemical scaffold for LSD1 inhibitors, and also provide new insight into the anti-NSCLC action of sanguinarine.
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Affiliation(s)
- Ting-ting Qin
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Zhong-hua Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Li-xin Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Kun Du
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Ji-ge Yang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Zhen-qiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Xiang-xiang Wu
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China ,Corresponding authors: Xiang-xiang Wu. Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. ; Jin-lian Ma. Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
| | - Jin-lian Ma
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China ,Corresponding authors: Xiang-xiang Wu. Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. ; Jin-lian Ma. Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
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Design, synthesis and biological studies of some new imidazole-1,2,3-triazole hybrid derivatives. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Liu J, Zhu X, Yu L, Mao M. Discovery of novel sulphonamide hybrids that inhibit LSD1 against bladder cancer cells. J Enzyme Inhib Med Chem 2022; 37:866-875. [PMID: 35350943 PMCID: PMC8973347 DOI: 10.1080/14756366.2021.2014830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Aim:A series of sulphonamide hybrids were designed, synthesised, and identified as potential lysine-specific demethylase 1 (LSD1) inhibitors. Materials and methods: Bladder cancer cell lines were cultured to evaluate the antiproliferative activity. Inhibitory evaluation of sulphonamide hybrids against LSD1 were performed. Conclusion: sulphonamide derivative L8 exhibited the antiproliferative activity against HTB5, HTB3, HT1376, and HTB1 cells with IC50 values of 1.87, 0.18, 0.09, and 0.93 μM, respectively. Compound L8 as a selective and reversible LSD1 inhibitor could inhibit LSD1 with the IC50 value of 60 nM. It effectively inhibited LSD1 by increasing the expression levels of H3K4me1, H3K4me2, and H3K9me2 in HT1376 cells. To the best of our knowledge, this was the first report which showed that sulphonamide–quinoline–dithiocarbamate hybrids potently inhibited LSD1 in bladder cancer cells. Our studies give the potential application of the sulphonamide-based scaffold for developing LSD1 inhibitors to treat bladder cancer.
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Affiliation(s)
- Jia Liu
- Department of Urology, The 4th affiliated hospital of China Medical University, Shenyang, PR China
| | - Xingwang Zhu
- Department of Urology, The 4th affiliated hospital of China Medical University, Shenyang, PR China
| | - Liu Yu
- Department of Urology, The 4th affiliated hospital of China Medical University, Shenyang, PR China
| | - Minghuan Mao
- Department of Urology, The 4th affiliated hospital of China Medical University, Shenyang, PR China
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Shen DD, Pang JR, Bi YP, Zhao LF, Li YR, Zhao LJ, Gao Y, Wang B, Wang N, Wei L, Guo H, Liu HM, Zheng YC. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer. Mol Cancer 2022; 21:75. [PMID: 35296335 PMCID: PMC8925194 DOI: 10.1186/s12943-022-01557-1] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/01/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. METHODS Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). RESULTS Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. CONCLUSION LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.
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Affiliation(s)
- Dan-Dan Shen
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Jing-Ru Pang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Ya-Ping Bi
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Long-Fei Zhao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Yin-Rui Li
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Li-Juan Zhao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, China
| | - Ya Gao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Bo Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China
| | - Ning Wang
- The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang, Hebei, China
| | - Huiqin Guo
- Thoracic Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hong-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China.
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, China.
| | - Yi-Chao Zheng
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China.
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, China.
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Zhao LF, Qi FY, Zhang JG, Pang JR, Ren HM, Shen DD, Zhao LJ, Qi L, Liu HM, Zheng YC. Identification of the upstream regulators of KDM5B in gastric cancer. Life Sci 2022; 298:120458. [DOI: 10.1016/j.lfs.2022.120458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/19/2022] [Accepted: 03/01/2022] [Indexed: 02/03/2023]
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Tang SY, Zhou PJ, Meng Y, Zeng FR, Deng GT. Gastric cancer: An epigenetic view. World J Gastrointest Oncol 2022; 14:90-109. [PMID: 35116105 PMCID: PMC8790429 DOI: 10.4251/wjgo.v14.i1.90] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.
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Affiliation(s)
- Si-Yuan Tang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Pei-Jun Zhou
- Cancer Research Institute, School of Basic Medicine Science, Central South University, School of Basic Medicine Science, Central South University 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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Liang Q, Liu M, Li J, Tong R, Hu Y, Bai L, Shi J. NAE modulators: A potential therapy for gastric carcinoma. Eur J Med Chem 2022; 231:114156. [DOI: 10.1016/j.ejmech.2022.114156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/15/2022] [Accepted: 01/24/2022] [Indexed: 12/24/2022]
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40
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Sun YX, Song J, Kong LJ, Sha BB, Tian XY, Liu XJ, Hu T, Chen P, Zhang SY. Design, synthesis and evaluation of novel bis-substituted aromatic amide dithiocarbamate derivatives as colchicine site tubulin polymerization inhibitors with potent anticancer activities. Eur J Med Chem 2021; 229:114069. [PMID: 34971875 DOI: 10.1016/j.ejmech.2021.114069] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/18/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
As the continuation of our work on the development of tubulin inhibitors with potential anticancer activities, novel bis-substituted aromatic amide dithiocarbamate derivatives were designed by contacting bis-substituted aryl scaffolds (potential anti-tubulin fragments) with N-containing heterocycles (potential anti-tubulin fragments) in one hybrid using the anticancer dithioformate unit as the linker. The antiproliferative activity against three digestive tract tumor cells was evaluated and preliminary structure activity relationships were summarized. Among these compounds, compound 20q exhibited most potent antiproliferative activity against MGC-803, HCT-116, Kyse30 and Kyse450 cells with IC50 values of 0.084, 0.227, 0.069 and 0.078 μM, respectively. In further studies, compound 20q was identified as a novel tubulin inhibitor targeting the colchicine binding site. Compound 20q could inhibit the microtubule assembly and disrupt cytoskeleton in Kyse30 and Kyse450 cells. The results of molecular docking suggested that compound 20q could tightly bind into the colchicine binding site of tubulin by hydrogen bonds and hydrophobic interactions. Compound 20q dose-dependently inhibited the cell growth and colony formation, effectively arrested cells at the G2/M phase and induce mitochondrial apoptosis in Kyse30 and Kyse450 cells. In addition, Compound 20q could regulate the expression of G2/M phase and mitochondrial apoptosis related proteins. Collectively, compound 20q was here reported as a novel tubulin inhibitor with potential anticancer activities.
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Affiliation(s)
- Ya-Xin Sun
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Li-Jun Kong
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Bei-Bei Sha
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xin-Yi Tian
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiu-Juan Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Tao Hu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Ping Chen
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, Jiangsu, People's Republic of China.
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Song Z, Gao K, Asmamaw MD, Liu YJ, Zheng YC, Shi XJ, Liu HM. Discovery of the antitumor activities of a potent DCN1 inhibitor compound 383 targeting LSD1 in gastric cancer. Eur J Pharmacol 2021; 916:174725. [PMID: 34953802 DOI: 10.1016/j.ejphar.2021.174725] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/03/2022]
Abstract
Dual target compounds have become a hot spot in the treatment of cancer in recent years. Histone lysine specific demethylase 1 (LSD1) is identified as histone demethylase and acts as a key regulator involved in many other cellular activities through its demethylation function. We have reported a triazolo [1,5-α] pyrimidine-based DCN1(defective in cullin neddylation protein 1) inhibitor compound 383 (IC50 = 11 nM) which could selectively inhibit Cullin 3/1 neddylation in MGC-803 cells. In this research, we investigated that compound 383 could target LSD1 and inhibit the biological function of LSD1 in MGC-803 cells (IC50 = 0.53 μM). We found that compound 383 could induce the degradation of LSD1 and inhibit MGC-803 cell proliferation, migration and invasion in a dose-dependent manner. Compound 383 could cause cell cycle arrest at G2/M phase by down-regulating the expression of LSD1. In addition, compound 383 could significantly reverse epithelial-mesenchymal transition (EMT) through increase H3K4me methylation at E-cadherin promotor. Furthermore, the in vivo inhibitory effect of compound 383 without obvious toxicity was confirmed in nude mouse transplanted MGC-803 tumor cells model. Collectively, these results suggest that the DCN1 inhibitor compound 383 exhibits antiproliferative activity in gastric cancer cells by targeting LSD1 which promotes compound 383 as a good starting point for the development of dual-target therapeutics for gastric cancer.
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Affiliation(s)
- Zan Song
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Ke Gao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Moges Dessale Asmamaw
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yue-Jiao Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiao-Jing Shi
- Laboratory Animal Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China.
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Li Z, Qin T, Li Z, Zhao X, Zhang X, Zhao T, Yang N, Miao J, Ma J, Zhang Z. Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing. Eur J Med Chem 2021; 225:113778. [PMID: 34416665 DOI: 10.1016/j.ejmech.2021.113778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/29/2021] [Accepted: 08/12/2021] [Indexed: 01/09/2023]
Abstract
Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
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Affiliation(s)
- Zhonghua Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Tingting Qin
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Zhongrui Li
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Xuan Zhao
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xinhui Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Taoqian Zhao
- Department of Chemistry, National University of Singapore, 117543, Singapore
| | - Nian Yang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Jinxin Miao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Jinlian Ma
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Zhenqiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
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Ding L, Wei F, Wang N, Sun Y, Wang Q, Fan X, Qi L, Wang S. Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer. J Enzyme Inhib Med Chem 2021; 36:1563-1572. [PMID: 34281464 PMCID: PMC8291071 DOI: 10.1080/14756366.2021.1917564] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/11/2021] [Accepted: 04/01/2021] [Indexed: 01/14/2023] Open
Abstract
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.
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Affiliation(s)
- Lijuan Ding
- The First Hospital of Jilin University, Changchun, China
| | - Feng Wei
- The First Hospital of Jilin University, Changchun, China
| | - Nanya Wang
- The First Hospital of Jilin University, Changchun, China
| | - Yue Sun
- The First Hospital of Jilin University, Changchun, China
| | - Qiang Wang
- The First Hospital of Jilin University, Changchun, China
| | - Xia Fan
- The First Hospital of Jilin University, Changchun, China
| | - Ling Qi
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
| | - Shudong Wang
- The First Hospital of Jilin University, Changchun, China
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Intermolecular insights into allosteric inhibition of histone lysine-specific demethylase 1. Biochim Biophys Acta Gen Subj 2021; 1865:129990. [PMID: 34390793 DOI: 10.1016/j.bbagen.2021.129990] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Histone lysine-specific demethylase 1 (LSD1) has become a potential anticancer target for the novel drug discovery. Recent reports have shown that SP2509 and its derivatives strongly inhibit LSD1 as allosteric inhibitors. However, the binding mechanism of these allosteric inhibitors in the allosteric site of LSD1 is not known yet. METHODS The stability and binding mechanism of allosteric inhibitors in the binding site of LSD1 were evaluated by molecular docking, ligand-based pharmacophore, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM/GBSA) analysis, quantum mechanics/molecular mechanics (QM/MM) calculation and Hirshfeld surface analysis. RESULTS The conformational geometry and the intermolecular interactions of allosteric inhibitors showed high binding affinity towards allosteric site of LSD1 with the neighboring amino acids (Gly358, Cys360, Leu362, Asp375 and Glu379). Meanwhile, MD simulations and MM/GBSA analysis were performed on selected allosteric inhibitors in complex with LSD1 protein, which confirmed the high stability and binding affinity of these inhibitors in the allosteric site of LSD1. CONCLUSION The simulation results revealed the crucial factors accounting for allosteric inhibitors of LSD1, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. Meanwhile, a halogen bond interaction between chlorine atom of ligand and key residues Trp531 and His532 was recurrent in our analysis confirming its importance. GENERAL SIGNIFICANCE Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.
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Zheng YC, Liu YJ, Gao Y, Wang B, Liu HM. An Update of Lysine Specific Demethylase 1 Inhibitor: A Patent Review (2016-2020). Recent Pat Anticancer Drug Discov 2021; 17:9-25. [PMID: 34323202 DOI: 10.2174/1574892816666210728125224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND As a FAD (Flavin Adenine Dinucleotide) - dependent histone demethylase discovered in 2004, LSD1 (lysine specific demethylase 1) was reported to be overexpressed in diverse tumors, regulating target genes transcription associated with cancer development. Hence, LSD1 targeted inhibitors may represent a new insight in anticancer drug discovery. For these reasons, researchers in both the pharmaceutical industry and academia have been actively pursuing LSD1 inhibitors in the quest for new anti-cancer drugs. OBJECTIVES This review summaries patents about LSD1 inhibitors in recent 5 years in hope of providing a reference for LSD1 researchers to develop new modulators of LSD1 with higher potency and fewer adverse effects. METHODS This review collects LSD1 inhibitors disclosed in patents since 2016. The primary ways of patent searching are Espacenet®, Google Patents, and CNKI. RESULTS This review covers dozens of patents related to LSD1 inhibitors in recent five years. The compound structures are mainly divided into TCP (Tranylcypromine) derivatives, imidazole derivatives, pyrimidine derivatives, and other natural products and peptides. Meanwhile, the compounds that have entered the clinical phase are also described. CONCLUSION Most of the compounds in these patents have been subjected to activity analysis with LSD1 and multi-cell lines, showing good antitumor activity in vitro and in vivo. These patents exhibited the structural diversity of LSD1 inhibitors and the potential of natural products as novel LSD1 inhibitors.
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Affiliation(s)
- Yi-Chao Zheng
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Yue-Jiao Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Ya Gao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Bo Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Hong-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
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Design and identification of two novel resveratrol derivatives as potential LSD1 inhibitors. Future Med Chem 2021; 13:1415-1433. [PMID: 34232085 DOI: 10.4155/fmc-2021-0105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background: Overexpression of LSD1 is associated with the occurrence of many diseases, including cancers, which makes LSD1 a significant target for anticancer drug research. Methodology & Results: With the aid of 3D quantitative structure-activity relationship models established with 34 reported resveratrol derivative LSD1 inhibitors, derivatives 35-40 were designed. Absorption, distribution, metabolism and excretion calculations showed that they may have good bioavailability and drug likeness. Additionally, 35 and 37 presented good antitumor effects in an in vitro antiproliferative assay. Molecular docking and molecular dynamics simulation results indicated that 35 and 37 can establish extensive interactions with LSD1. Conclusion: The results of computational prediction and experimental validation suggest that 35 and 37 are effective antitumor inhibitors, which provides some ideas and directions for the development of new anticancer LSD1 inhibitors.
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Li Y, Sun Y, Zhou Y, Li X, Zhang H, Zhang G. Discovery of orally active chalcones as histone lysine specific demethylase 1 inhibitors for the treatment of leukaemia. J Enzyme Inhib Med Chem 2021; 36:207-217. [PMID: 33307878 PMCID: PMC7738283 DOI: 10.1080/14756366.2020.1852556] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Histone lysine specific demethylase 1 (LSD1) has emerged as an attractive molecule target for the discovery of potently anticancer drugs to treat leukaemia. In this study, a series of novel chalcone derivatives were designed, synthesised and evaluated for their inhibitory activities against LSD1 in vitro. Among all these compounds, D6 displayed the best LSD1 inhibitory activity with an IC50 value of 0.14 μM. In the cellular level, compound D6 can induce the accumulation of H3K9me1/2 and inhibit cell proliferation by inactivating LSD1. It exhibited the potent antiproliferative activity with IC50 values of 1.10 μM, 3.64 μM, 3.85 μM, 1.87 μM, 0.87 μM and 2.73 μM against HAL-01, KE-37, P30-OHK, SUP-B15, MOLT-4 and LC4-1 cells, respectively. Importantly, compound D6 significantly suppressed MOLT-4 xenograft tumour growth in vivo, indicating its great potential as an orally bioavailable candidate for leukaemia therapy.
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Affiliation(s)
- Yang Li
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Sun
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang Zhou
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xinyang Li
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Huan Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Guojun Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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Zhao LJ, Li YY, Zhang YT, Fan QQ, Ren HM, Zhang C, Mardinoglu A, Chen WC, Pang JR, Shen DD, Wang JW, Zhao LF, Zhang JY, Wang ZY, Zheng YC, Liu HM. Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness. EMBO Rep 2021; 22:e50922. [PMID: 34060205 DOI: 10.15252/embr.202050922] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 05/08/2021] [Accepted: 05/11/2021] [Indexed: 01/08/2023] Open
Abstract
Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.
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Affiliation(s)
- Li-Juan Zhao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Ying-Ying Li
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Yu-Tong Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Qi-Qi Fan
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Hong-Mei Ren
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome Interactions, King's College London, London, UK
| | - Wen-Chao Chen
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing-Ru Pang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Dan-Dan Shen
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Jun-Wei Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Long-Fei Zhao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Jian-Ying Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhen-Ya Wang
- Key Laboratory of "Runliang" Antiviral Medicines Research and Development, Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
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Dai XJ, Liu Y, Xue LP, Xiong XP, Zhou Y, Zheng YC, Liu HM. Correction to "Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1". J Med Chem 2021; 64:6410-6411. [PMID: 33871995 DOI: 10.1021/acs.jmedchem.0c02176] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer. Eur J Med Chem 2021; 220:113453. [PMID: 33957387 DOI: 10.1016/j.ejmech.2021.113453] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 03/14/2021] [Accepted: 03/15/2021] [Indexed: 12/16/2022]
Abstract
LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent antiproliferative activities against MGC-803 and HCT-116 cancer cell lines. Notably, compound 5m showed superior in vitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP-2509 with IC50 values ranging from 0.23 to 1.56 μM. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced apoptosis, reduced colony formation and suppressed migration in MGC-803 cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.
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