1
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Cao D, Liu G, Wang Y, Xia X. Repurposing astemizole to kill multidrug-resistant bacteria isolated in general surgery. Microb Pathog 2025; 200:107369. [PMID: 39929397 DOI: 10.1016/j.micpath.2025.107369] [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: 10/25/2024] [Revised: 01/31/2025] [Accepted: 02/07/2025] [Indexed: 02/13/2025]
Abstract
Antibiotic resistance has become a significant global public health challenge, particularly in general surgery, where infections caused by resistant bacteria complicate treatment. This study aims to evaluate the potential of the FDA-disapproved antihistamine astemizole as an antibacterial agent, with a focus on its efficacy against methicillin-resistant S. aureus (MRSA). Astemizole demonstrated significant activity against Gram-positive bacteria, especially MRSA, with MIC and MBC values ranging from 4 to 16 μg/mL and 4-32 μg/mL, respectively. However, astemizole showed minimal activity against Gram-negative bacteria. Further investigations revealed that astemizole killed bacteria by disrupting the bacterial membrane, altering membrane potential, inhibiting ATP production, and inducing reactive oxygen species accumulation. Additionally, The resistance mutation frequency of astemizole was low, with only a minor increase in resistance observed in MRSA after 30 days of selective pressure, significantly less than that of ampicillin. Cytotoxicity and hemolysis assays indicated that astemizole was relatively safe at concentrations effective for bacterial inhibition. The Galleria mellonella infection model further confirmed the efficacy of astemizole against MRSA in vivo. Overall, this study provides new insights into the repurposing of astemizole and suggests its potential as a therapeutic agent to address antibiotic resistance.
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Affiliation(s)
- Daxing Cao
- Department of Infectious Diseases, Changxing County People's Hospital, Huzhou, 313100, China.
| | - Guihua Liu
- Department of Infectious Diseases, Changxing County People's Hospital, Huzhou, 313100, China.
| | - Ying Wang
- Department of Infectious Diseases, Changxing County People's Hospital, Huzhou, 313100, China.
| | - Xiaoxue Xia
- Department of Infectious Diseases, Changxing County People's Hospital, Huzhou, 313100, China.
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2
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Cheng S, Li J, Song YQ, Jing S, Lan YX, Wang L, Chan DSH, Wong CY, Sheng C, Wang W, Wang HMD, Leung CH. A Bioactive Benzimidazole-Cyclometalated Iridium(III) Complex as an Epigenetic Regulator through Effectively Interrupting the EED-EZH2 Interaction. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2405771. [PMID: 39967436 DOI: 10.1002/smll.202405771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/24/2025] [Indexed: 02/20/2025]
Abstract
Epigenetic regulation plays a fundamental role in controlling gene expression and maintaining cellular identity. Among epigenetic processes, the translocation of methyltransferases is critical for the modification of chromatin structure and transcriptional activity. The regulation of these translocation events and the mechanisms involved are complex, yet critical for understanding and manipulating epigenetic states. Therefore, novel strategies are required for detecting and visualizing the movement and interaction of methyltransferases within cells. Using enhancer of zeste homolog 2 (EZH2) methyltransferase as an example, a bifunctional compound capable of both monitoring and disrupting its translocation process is developed by targeting the protein-protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2. The Ir(III) complex 1 bound enthalpically to EED and effectively inhibited the methyltransferase activity of EZH2. Moreover, disruption of the EED-EZH2 PPI led to increased transcriptional activity of P21 and P27, resulting in the suppression of triple-negative breast cancer (TNBC) cell proliferation. Excitingly, 1 suppressed tumor metastasis in a TNBC mouse model in vivo. To our knowledge, complex 1 is the first metal-based bifunctional therapeutic agent designed to probe and inhibit the EED-EZH2 PPI, highlighting the feasibility and significance of using metal complexes to monitor and influence methyltransferase translocations for therapeutic applications.
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Grants
- MYRG-GRG2024-00202-ICMS-UMDF the University of Macau, University of Macau Development Foundation, Macau SAR, China
- MYRG-GRG2023-00194-ICMS-UMDF the University of Macau, University of Macau Development Foundation, Macau SAR, China
- SKL-QRCM-IRG2023-025 State Key Laboratory of Quality Research in Chinese Medicine, the University of Macau, Macau SAR, China
- 22101230 National Natural Science Foundation of China
- 22077109 National Natural Science Foundation of China
- 21775131 National Natural Science Foundation of China
- 2024SF-YBXM-418 Key Research and Development Program of Shaanxi
- 2023YFE0205200 National Key Research and Development Program of China
- D5000230060 Fundamental Research Funds for the Central Universities
- 2023-CX-TD-72 Innovation Capability Support Program of Shaanxi
- ZDYF2021SHFZ250 Hainan Province Science and Technology Special Fund
- 2023A1515011871 Basic and Applied Basic Research Foundation of Guangdong Province
- SKL-QRCM(UM)-2023-2025,0020/2022/A1,0045/2023/AMJ,0032/2023/RIB2 the Science and Technology Development Fund, Macau SAR, China
- 111-2221-E-005-026-MY3,111-2221-E-005-009 the Ministry of Science and Technology (MOST), Taiwan
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Affiliation(s)
- Shasha Cheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | - Jian Li
- College of Food and Biological Engineering, Jimei University, Xiamen, 361021, China
| | - Ying-Qi Song
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Shaozhen Jing
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, 45 South Gaoxin Road, Shenzhen, 518057, China
| | - Yi-Xuan Lan
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 402, Taiwan
| | - Ling Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | | | - Chun-Yuen Wong
- Department of Chemistry, City University of Hong Kong, Hong Kong, 999077, China
| | - Chunquan Sheng
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
- The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai, 200433, China
| | - Wanhe Wang
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, 45 South Gaoxin Road, Shenzhen, 518057, China
| | - Hui-Min David Wang
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 402, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, 404, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, 701, Taiwan
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
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3
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Ji Y, Chen Z, Cai J. Roles and mechanisms of histone methylation in vascular aging and related diseases. Clin Epigenetics 2025; 17:35. [PMID: 39988699 PMCID: PMC11849368 DOI: 10.1186/s13148-025-01842-y] [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: 11/20/2024] [Accepted: 02/14/2025] [Indexed: 02/25/2025] Open
Abstract
The global aging trend has posed significant challenges, rendering healthcare for older adults a crucial focus in medical research. Among the numerous health concerns related to aging, vascular aging and dysfunction are important risk factors and underlying causes of age-related diseases. Histone methylation and demethylation, which are involved in gene expression and cellular senescence, are closely associated with the occurrence and development of vascular aging. Consequently, this review aimed to identify the role of histone methylation in the pathogenesis of vascular aging and its potential for treating age-related vascular diseases and provided new insights into therapeutic strategies targeting the vascular system.
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Affiliation(s)
- Yufei Ji
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Peking Union Medical College, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhenzhen Chen
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Jun Cai
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Peking Union Medical College, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China.
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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4
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Perumal N, Gopalakrishnan P, Burkovetskaya M, Doss D, Dukkipati SS, Kanchan RK, Mahapatra S. Nuclear factor I/B: Duality in action in cancer pathophysiology. Cancer Lett 2025; 609:217349. [PMID: 39581218 DOI: 10.1016/j.canlet.2024.217349] [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: 07/07/2024] [Revised: 11/15/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
The nuclear factor I (NFI) family of transcription factors plays a decisive role in organ development and maturation. Their deregulation has been linked with various diseases, most notably cancer. NFIB stands apart from the other NFI family members given its unique ability to drive both tumor suppressive and oncogenic programs. Thus, the ultimate impact of deregulated NFIB signaling is cancer-specific and strongly influenced by an intricate network of upstream regulators and downstream effectors. Deciphering the events that drive NFIB's paradoxical roles within these networks will enable us to not only understand how this critical transcription factor enacts its dual roles but also drive innovations to help us effectively target NFIB in different cancers. Here, we provide an in-depth review of NFIB. Starting with its defining role in the development of various organs, most notably the central nervous system, we highlight critical signaling pathways and the impact of deregulation on neoplastic transformation, contrasting it with the effect of silencing alone. We then provide examples of its dual roles in various cancers, identifying specific signaling networks associated with oncogenesis versus tumor suppression. We incorporate an example of a cancer type, osteosarcoma, wherein NFIB enacts its dual functions and explore which pathways influence each function. In this manner, we suggest plausible mechanisms for its role-switching from cancers sharing common triggering events in the setting of NFIB deregulation. We also review how NFIB enhances aggressiveness by driving metastasis, stemness, and chemoresistance. We conclude with a discussion on efficacious ways to target NFIB and pose some unanswered questions that may further help solidify our understanding of NFIB and facilitate clinical translation of NFIB targeting.
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Affiliation(s)
- Naveenkumar Perumal
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Prakadeeswari Gopalakrishnan
- Department of Ophthalmology, Center for Translational Vision Research, Gavin Herbert Eye Institute, University of California, Irvine, CA, USA
| | - Maria Burkovetskaya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - David Doss
- School of Medicine, Creighton University, Omaha, NE, USA
| | - S Shekar Dukkipati
- Department of Pediatrics, Columbia University Irving Medical Center, New York City, NY, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
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5
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Wagih N, Abdel-Rahman IM, El-Koussi NA, El-Din A Abuo-Rahma G. Anticancer benzimidazole derivatives as inhibitors of epigenetic targets: a review article. RSC Adv 2025; 15:966-1010. [PMID: 39807197 PMCID: PMC11726184 DOI: 10.1039/d4ra05014b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide. One of the primary causes of cancer development and progression is epigenetic dysregulation, which is a heritable modification that alters gene expression without changing the DNA sequence. Therefore, targeting these epigenetic changes has emerged as a promising therapeutic strategy. Benzimidazole derivatives have gained attention for their potent epigenetic modulatory effects as they interact with various epigenetic targets, including DNA methyltransferases, histone deacetylases and histone methyltransferases. This review provides a comprehensive overview of benzimidazole derivatives that inhibit different acetylation and methylation reader, writer and eraser epigenetic targets. Herein, we emphasize the therapeutic potential of these compounds in developing targeted, less toxic cancer therapies. Presently, some promising benzimidazole derivatives have entered clinical trials and shown great advancements in the fields of hematological and solid malignancy therapies. Accordingly, we highlight the recent advancements in benzimidazole research as epigenetic agents that could pave the way for designing new multi-target drugs to overcome resistance and improve clinical outcomes for cancer patients. This review can help researchers in designing new anticancer benzimidazole derivatives with better properties.
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Affiliation(s)
- Nardin Wagih
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
| | - Islam M Abdel-Rahman
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
| | - Nawal A El-Koussi
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
- Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University 71526 Assiut Egypt
| | - Gamal El-Din A Abuo-Rahma
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University 61519 Minia Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
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6
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Wozniak M, Czyz M. Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities. Ther Adv Med Oncol 2025; 17:17588359241306026. [PMID: 39776536 PMCID: PMC11705335 DOI: 10.1177/17588359241306026] [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] [Received: 06/20/2024] [Accepted: 11/21/2024] [Indexed: 01/11/2025] Open
Abstract
The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. EZH2 is frequently mutated and/or its expression is deregulated in various cancer types. The cancer sensitivity to inhibitors of EZH2 enzymatic activity and state-of-the-art approaches to deplete EZH2 with chemical degraders are discussed. This review also presents the clinical trials in various phases that evaluate the use of EZH2 inhibitors, both as monotherapy and in combination with other agents for the treatment of patients with diverse types of cancers.
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Affiliation(s)
- Michal Wozniak
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland
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7
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Chang Y, Guo H, Li X, Zong L, Wei J, Li Z, Luo C, Yang X, Fang H, Kong X, Hou X. Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity. J Med Chem 2024; 67:16480-16504. [PMID: 39264152 DOI: 10.1021/acs.jmedchem.4c01310] [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: 09/13/2024]
Abstract
Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.
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Affiliation(s)
- Yingjie Chang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, China
| | - Huahui Guo
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China
| | - Xue Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, China
| | - Liangyi Zong
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China
| | - Jiale Wei
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Zhihai Li
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Cheng Luo
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Xinying Yang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, China
| | - Hao Fang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, China
| | - Xiangqian Kong
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China
| | - Xuben Hou
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, China
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8
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Bao Q, Kumar A, Wu D, Zhou J. Targeting EED as a key PRC2 complex mediator toward novel epigenetic therapeutics. Drug Discov Today 2024; 29:103986. [PMID: 38642703 PMCID: PMC11416859 DOI: 10.1016/j.drudis.2024.103986] [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: 02/23/2024] [Revised: 04/06/2024] [Accepted: 04/15/2024] [Indexed: 04/22/2024]
Abstract
EED within the PRC2 complex is crucial for chromatin regulation particularly in tumor development, making its inhibition a promising epigenetic therapeutic strategy. Significant advancement in PRC2 inhibitor development has been achieved with an approved EZH2 inhibitor in the market and with others in the clinical trials. However, current EZH2 inhibitors are limited to specific blood cancers and encounter therapeutic resistance. EED stabilizes PRC2 complex and enhances its activity through unique allosteric mechanisms, thereby acting as both a scaffold protein and a recognizer of H3K27me3 making it an attractive drug target. This review provides an overview of epigenetic therapeutic strategies targeting EED, including allosteric inhibitors, PPI inhibitors, and PROTACs, together with brief discussions on the relevant challenges, opportunities, and future directions.
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Affiliation(s)
- Qichao Bao
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Anil Kumar
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Daqing Wu
- Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
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9
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Huang X, Chen Y, Xiao Q, Shang X, Liu Y. Chemical inhibitors targeting histone methylation readers. Pharmacol Ther 2024; 256:108614. [PMID: 38401773 DOI: 10.1016/j.pharmthera.2024.108614] [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: 12/19/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/26/2024]
Abstract
Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and potential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.
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Affiliation(s)
- Xiaolei Huang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yichang Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Qin Xiao
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Xinci Shang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yanli Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China.
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10
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Guo Y, Cheng R, Wang Y, Gonzalez ME, Zhang H, Liu Y, Kleer CG, Xue L. Regulation of EZH2 protein stability: new mechanisms, roles in tumorigenesis, and roads to the clinic. EBioMedicine 2024; 100:104972. [PMID: 38244292 PMCID: PMC10835131 DOI: 10.1016/j.ebiom.2024.104972] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/13/2023] [Accepted: 01/04/2024] [Indexed: 01/22/2024] Open
Abstract
The importance of EZH2 as a key methyltransferase has been well documented theoretically. Practically, the first EZH2 inhibitor Tazemetostat (EPZ6438), was approved by FDA in 2020 and is used in clinic. However, for most solid tumors it is not as effective as desired and the scope of clinical indications is limited, suggesting that targeting its enzymatic activity may not be sufficient. Recent technologies focusing on the degradation of EZH2 protein have drawn attention due to their potential robust effects. This review focuses on the molecular mechanisms that regulate EZH2 protein stability via post-translational modifications (PTMs), mainly including ubiquitination, phosphorylation, and acetylation. In addition, we discuss recent advancements of multiple proteolysis targeting chimeras (PROTACs) strategies and the latest degraders that can downregulate EZH2 protein. We aim to highlight future directions to expand the application of novel EZH2 inhibitors by targeting both EZH2 enzymatic activity and protein stability.
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Affiliation(s)
- Yunyun Guo
- Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Rui Cheng
- Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Yuqing Wang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Maria E Gonzalez
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Hongshan Zhang
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Yang Liu
- Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
| | - Celina G Kleer
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
| | - Lixiang Xue
- Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
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11
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Wang D, Guo Q, Wu Z, Li M, He B, Du Y, Zhang K, Tao Y. Molecular mechanism of antihistamines recognition and regulation of the histamine H 1 receptor. Nat Commun 2024; 15:84. [PMID: 38167898 PMCID: PMC10762250 DOI: 10.1038/s41467-023-44477-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H1 receptor (H1R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H1R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H1R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H1R, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W4286.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.
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Affiliation(s)
- Dandan Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P. R. China
| | - Qiong Guo
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P. R. China
| | - Zhangsong Wu
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China
| | - Ming Li
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P. R. China
| | - Binbin He
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P. R. China
| | - Yang Du
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China
| | - Kaiming Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P. R. China.
| | - Yuyong Tao
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P. R. China.
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12
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Chandnani N, Gupta I, Thakkar V, Sarkar K. Epigenetic regulation of enhancer of zeste homolog 2 (EZH2) -Yin Yang 1 (YY1) axis in cancer. Pathol Res Pract 2023; 251:154885. [PMID: 37862922 DOI: 10.1016/j.prp.2023.154885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 10/22/2023]
Abstract
In accordance with the World Health Organization, cancer is the second leading cause of death in patients. In recent years, the number of cancer patients has been growing, and the occurrence of cancer in people is becoming more common, primarily due to lifestyle factors. Yin Yang 1 (YY1) is a transcription factor that is widespread throughout. It is a zinc finger protein, falling under the GLI-Kruppel class. YY1 is known to regulate transcriptional activation and repression of various genes associated with different cellular processes such as DNA repair, autophagy, cell survival and apoptosis, and cell division. Meanwhile, EZH2 is a histone-lysine N-methyltransferase enzyme encoded by gene 7 in humans. Its main function involves catalyzing the addition of methyl groups to histone H3 at lysine 27 (H3K27me3), and it is involved in regulating CD8 + T cell fate and function. It is a subunit of a Polycomb repressor complex 2 (PRC2). The EZH2 gene encodes for an enzyme that is involved in histone methylation and transcriptional repression. It adds methyl groups to lysine 27 on histone H3 (H3K27me3) with the help of the cofactor S-adenosyl-L-methionine. In addition to its role in epigenetic regulation, EZH2 also acts as a regulator of CD8+ T cell fate and function. EZH2 has been implicated in T Cell Receptor (TCR) signaling via the regulation of actin polymerization. In fact, EZH2 is involved in numerous signaling pathways that lead to tumorigenesis. EZH2 is mutated in cancer and shows overexpression. Due to its mutation and overexpression, the cells that help combat cancer are suppressed and carcinogenicity is promoted. The association of EZH2 and YY1 poses an intriguing mechanism in relation to cancer.
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Affiliation(s)
- Nikhil Chandnani
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Ishika Gupta
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Vidhi Thakkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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13
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Giuliano S, Montemagno C, Domdom MA, Teisseire M, Brest P, Klionsky DJ, Hofman P, Pagès G, Mograbi B. Should evidence of an autolysosomal de-acidification defect in Alzheimer and Parkinson diseases call for caution in prescribing chronic PPI and DMARD? Autophagy 2023; 19:2800-2806. [PMID: 37482676 PMCID: PMC10472882 DOI: 10.1080/15548627.2023.2214960] [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: 09/14/2022] [Revised: 04/18/2023] [Accepted: 05/08/2023] [Indexed: 07/25/2023] Open
Abstract
Nearly fifty million older people suffer from neurodegenerative diseases, including Alzheimer (AD) and Parkinson (PD) disease, a global burden expected to triple by 2050. Such an imminent "neurological pandemic" urges the identification of environmental risk factors that are hopefully avoided to fight the disease. In 2022, strong evidence in mouse models incriminated defective lysosomal acidification and impairment of the autophagy pathway as modifiable risk factors for dementia. To date, the most prescribed lysosomotropic drugs are proton pump inhibitors (PPIs), chloroquine (CQ), and the related hydroxychloroquine (HCQ), which belong to the group of disease-modifying antirheumatic drugs (DMARDs). This commentary aims to open the discussion on the possible mechanisms connecting the long-term prescribing of these drugs to the elderly and the incidence of neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; APP-βCTF: amyloid beta precursor protein-C-terminal fragment; BACE1: beta-secretase 1; BBB: brain blood barrier; CHX: Ca2+/H+ exchanger; CMI: cognitive mild impairment; CQ: chloroquine; DMARD: disease-modifying antirheumatic drugs; GBA1: glucosylceramidase beta 1; HCQ: hydroxychloroquine; HPLC: high-performance liquid chromatography; LAMP: lysosomal associated membrane protein; MAPK/JNK: mitogen-activated protein kinase; MAPT: microtubule associated protein tau; MCOLN1/TRPML1: mucolipin TRP cation channel 1; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NRBF2: nuclear receptor binding factor 2; PANTHOS: poisonous flower; PD: Parkinson disease; PIK3C3: phosphatIdylinositol 3-kinase catalytic subunit type 3; PPI: proton pump inhibitor; PSEN1: presenilin 1, RUBCN: rubicon autophagy regulator; RUBCNL: rubicon like autophagy enhancer; SQSTM1: sequestosome 1; TMEM175: transmembrane protein 175; TPCN2: two pore segment channel 2; VATPase: vacuolar-type H+-translocating ATPase; VPS13C: vacuolar protein sorting ortholog 13 homolog C; VPS35: VPS35 retromer complex component; WDFY3: WD repeat and FYVE domain containing 3; ZFYVE1: zinc finger FYVE-type containing 1.
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Affiliation(s)
- Sandy Giuliano
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
| | | | - Marie-Angela Domdom
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
| | - Manon Teisseire
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
| | - Patrick Brest
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
| | - Daniel J. Klionsky
- Department of Molecular, Cellular, and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Paul Hofman
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
- CHU de Nice, laboratory of Clinical and Experimental Pathology (LPCE), Université Côte d’Azur, CNRS, INSERM, IRCAN, IHU RespirERA, FHU-Oncoage, Nice, France
| | - Gilles Pagès
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
| | - Baharia Mograbi
- Université Nice Côte d'Azur, IRCAN, CNRS, INSERM, Centre Antoine Lacassagne, IHU RespirERA, FHU-Oncoage, Nice, France
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14
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Campbell WA, El-Hodiri HM, Torres D, Hawthorn EC, Kelly LE, Volkov L, Akanonu D, Fischer AJ. Chromatin access regulates the formation of Müller glia-derived progenitor cells in the retina. Glia 2023; 71:1729-1754. [PMID: 36971459 PMCID: PMC11335016 DOI: 10.1002/glia.24366] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 03/06/2023] [Accepted: 03/12/2023] [Indexed: 03/29/2023]
Abstract
Chromatin access and epigenetic control over gene expression play important roles in regulating developmental processes. However, little is known about how chromatin access and epigenetic gene silencing influence mature glial cells and retinal regeneration. Herein, we investigate the expression and functions of S-adenosylhomocysteine hydrolase (SAHH; AHCY) and histone methyltransferases (HMTs) during the formation of Müller glia (MG)-derived progenitor cells (MGPCs) in the chick and mouse retinas. In chick, AHCY, AHCYL1 and AHCYL2, and many different HMTs are dynamically expressed by MG and MGPCs in damaged retinas. Inhibition of SAHH reduced levels of H3K27me3 and potently blocks the formation of proliferating MGPCs. By using a combination of single cell RNA-seq and single cell ATAC-seq, we find significant changes in gene expression and chromatin access in MG with SAHH inhibition and NMDA-treatment; many of these genes are associated with glial and neuronal differentiation. A strong correlation across gene expression, chromatin access, and transcription factor motif access in MG was observed for transcription factors known to convey glial identity and promote retinal development. By comparison, in the mouse retina, inhibition of SAHH has no influence on the differentiation of neuron-like cells from Ascl1-overexpressing MG. We conclude that in the chick the activity of SAHH and HMTs are required for the reprogramming of MG into MGPCs by regulating chromatin access to transcription factors associated with glial differentiation and retinal development.
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Affiliation(s)
- Warren A. Campbell
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Heithem M. El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Diego Torres
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Evan C. Hawthorn
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Lisa E. Kelly
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Leo Volkov
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - David Akanonu
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI
| | - Andy J. Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
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15
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Liu Y, Yang Q. The roles of EZH2 in cancer and its inhibitors. Med Oncol 2023; 40:167. [PMID: 37148376 PMCID: PMC10162908 DOI: 10.1007/s12032-023-02025-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/10/2023] [Indexed: 05/08/2023]
Abstract
The enhancer of zeste homolog 2 (EZH2) is encoded by the Enhancer of zeste 2 polycomb repressive complex 2 subunit gene. EZH2 is involved in the cell cycle, DNA damage repair, cell differentiation, autophagy, apoptosis, and immunological modulation. The main function of EZH2 is to catalyze the methylation of H3 histone of H3K27Me3, which inhibits the transcription of target genes, such as tumor suppressor genes. EZH2 also forms complexes with transcriptions factors or directly binds to the promoters of target genes, leading to regulate gene transcriptions. EZH2 has been as a prominent target for cancer therapy and a growing number of potential targeting medicines have been developed. This review summarized the mechanisms that EZH2 regulates gene transcription and the interactions between EZH2 and important intracellular signaling molecules (Wnt, Notch, MEK, Akt) and as well the clinical applications of EZH2-targeted drugs.
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Affiliation(s)
- Yuankai Liu
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China
| | - Qiong Yang
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China.
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16
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Ghate NB, Kim S, Shin Y, Kim J, Doche M, Valena S, Situ A, Kim S, Rhie SK, Lenz HJ, Ulmer TS, Mumenthaler SM, An W. Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer. Nat Commun 2023; 14:2140. [PMID: 37069142 PMCID: PMC10110550 DOI: 10.1038/s41467-023-37883-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 04/04/2023] [Indexed: 04/19/2023] Open
Abstract
Our recent work has shown that DCAF1 (also known as VprBP) is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether DCAF1 also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that DCAF1 phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, DCAF1-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a mechanism underlying DCAF1-driven colonic tumorigenesis by linking DCAF1-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.
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Affiliation(s)
- Nikhil B Ghate
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Sungmin Kim
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Yonghwan Shin
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jinman Kim
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Michael Doche
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90064, USA
| | - Scott Valena
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90064, USA
| | - Alan Situ
- Department of Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, 90033, USA
| | - Sangnam Kim
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Suhn K Rhie
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Tobias S Ulmer
- Department of Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, 90033, USA
| | - Shannon M Mumenthaler
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90064, USA
| | - Woojin An
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
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17
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Hanot M, Raby L, Völkel P, Le Bourhis X, Angrand PO. The Contribution of the Zebrafish Model to the Understanding of Polycomb Repression in Vertebrates. Int J Mol Sci 2023; 24:ijms24032322. [PMID: 36768643 PMCID: PMC9916924 DOI: 10.3390/ijms24032322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/20/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
Polycomb group (PcG) proteins are highly conserved proteins assembled into two major types of complexes, PRC1 and PRC2, involved in the epigenetic silencing of a wide range of gene expression programs regulating cell fate and tissue development. The crucial role of PRC1 and PRC2 in the fundamental cellular processes and their involvement in human pathologies such as cancer attracted intense attention over the last few decades. Here, we review recent advancements regarding PRC1 and PRC2 function using the zebrafish model. We point out that the unique characteristics of the zebrafish model provide an exceptional opportunity to increase our knowledge of the role of the PRC1 and PRC2 complexes in tissue development, in the maintenance of organ integrity and in pathology.
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Affiliation(s)
- Mariette Hanot
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Ludivine Raby
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Pamela Völkel
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Xuefen Le Bourhis
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Pierre-Olivier Angrand
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
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18
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Multiomics characteristics and immunotherapeutic potential of EZH2 in pan-cancer. Biosci Rep 2023; 43:232355. [PMID: 36545914 PMCID: PMC9842950 DOI: 10.1042/bsr20222230] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/29/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) is a significant epigenetic regulator that plays a critical role in the development and progression of cancer. However, the multiomics features and immunological effects of EZH2 in pan-cancer remain unclear. Transcriptome and clinical raw data of pan-cancer samples were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and subsequent data analyses were conducted by using R software (version 4.1.0). Furthermore, numerous bioinformatics analysis databases also reapplied to comprehensively explore and elucidate the oncogenic mechanism and therapeutic potential of EZH2 from pan-cancer insight. Finally, quantitative reverse transcription polymerase chain reaction and immunohistochemical assays were performed to verify the differential expression of EZH2 gene in various cancers at the mRNA and protein levels. EZH2 was widely expressed in multiple normal and tumor tissues, predominantly located in the nucleoplasm. Compared with matched normal tissues, EZH2 was aberrantly expressed in most cancers either at the mRNA or protein level, which might be caused by genetic mutations, DNA methylation, and protein phosphorylation. Additionally, EZH2 expression was correlated with clinical prognosis, and its up-regulation usually indicated poor survival outcomes in cancer patients. Subsequent analysis revealed that EZH2 could promote tumor immune evasion through T-cell dysfunction and T-cell exclusion. Furthermore, expression of EZH2 exhibited a strong correlation with several immunotherapy-associated responses (i.e., immune checkpoint molecules, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) status, and neoantigens), suggesting that EZH2 appeared to be a novel target for evaluating the therapeutic efficacy of immunotherapy.
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Abstract
Dynamic regulation of the chromatin state by Polycomb Repressive Complex 2 (PRC2) provides an important mean for epigenetic gene control that can profoundly influence normal development and cell lineage specification. PRC2 and PRC2-induced methylation of histone H3 lysine 27 (H3K27) are critically involved in a wide range of DNA-templated processes, which at least include transcriptional repression and gene imprinting, organization of three-dimensional chromatin structure, DNA replication and DNA damage response and repair. PRC2-based genome regulation often goes wrong in diseases, notably cancer. This chapter discusses about different modes-of-action through which PRC2 and EZH2, a catalytic subunit of PRC2, mediate (epi)genomic and transcriptomic regulation. We will also discuss about how alteration or mutation of the PRC2 core or axillary component promotes oncogenesis, how post-translational modification regulates functionality of EZH2 and PRC2, and how PRC2 and other epigenetic pathways crosstalk. Lastly, we will briefly touch on advances in targeting EZH2 and PRC2 dependence as cancer therapeutics.
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Affiliation(s)
- Yiran Guo
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
| | - Yao Yu
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Gang Greg Wang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
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20
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Mészáros B, Csoti A, Szanto TG, Telek A, Kovács K, Toth A, Volkó J, Panyi G. The hEag1 K + Channel Inhibitor Astemizole Stimulates Ca 2+ Deposition in SaOS-2 and MG-63 Osteosarcoma Cultures. Int J Mol Sci 2022; 23:ijms231810533. [PMID: 36142445 PMCID: PMC9504018 DOI: 10.3390/ijms231810533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/27/2022] [Accepted: 09/06/2022] [Indexed: 11/29/2022] Open
Abstract
The hEag1 (Kv10.1) K+ channel is normally found in the brain, but it is ectopically expressed in tumor cells, including osteosarcoma. Based on the pivotal role of ion channels in osteogenesis, we tested whether pharmacological modulation of hEag1 may affect osteogenic differentiation of osteosarcoma cell lines. Using molecular biology (RT-PCR), electrophysiology (patch-clamp) and pharmacology (astemizole sensitivity, IC50 = 0.135 μM) we demonstrated that SaOS-2 osteosarcoma cells also express hEag1 channels. SaOS-2 cells also express to KCa1.1 K+ channels as shown by mRNA expression and paxilline sensitivity of the current. The inhibition of hEag1 (2 μM astemizole) or KCa1.1 (1 mM TEA) alone did not induce Ca2+ deposition in SaOS-2 cultures, however, these inhibitors, at identical concentrations, increased Ca2+ deposition evoked by the classical or pathological (inorganic phosphate, Pi) induction pathway without causing cytotoxicity, as reported by three completer assays (LDH release, MTT assay and SRB protein assay). We observed a similar effect of astemizole on Ca2+ deposition in MG-63 osteosarcoma cultures as well. We propose that the increase in the osteogenic stimuli-induced mineral matrix formation of osteosarcoma cell lines by inhibiting hEag1 may be a useful tool to drive terminal differentiation of osteosarcoma.
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Affiliation(s)
- Beáta Mészáros
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Agota Csoti
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Tibor G. Szanto
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Andrea Telek
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Katalin Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Agnes Toth
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Julianna Volkó
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
| | - Gyorgy Panyi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Life Science Building, Egyetem Ter 1, H-4032 Debrecen, Hungary
- Correspondence: ; Tel.: +36-52-258603; Fax: +36-52-532201
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21
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Critical Roles of Polycomb Repressive Complexes in Transcription and Cancer. Int J Mol Sci 2022; 23:ijms23179574. [PMID: 36076977 PMCID: PMC9455514 DOI: 10.3390/ijms23179574] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
Polycomp group (PcG) proteins are members of highly conserved multiprotein complexes, recognized as gene transcriptional repressors during development and shown to play a role in various physiological and pathological processes. PcG proteins consist of two Polycomb repressive complexes (PRCs) with different enzymatic activities: Polycomb repressive complexes 1 (PRC1), a ubiquitin ligase, and Polycomb repressive complexes 2 (PRC2), a histone methyltransferase. Traditionally, PRCs have been described to be associated with transcriptional repression of homeotic genes, as well as gene transcription activating effects. Particularly in cancer, PRCs have been found to misregulate gene expression, not only depending on the function of the whole PRCs, but also through their separate subunits. In this review, we focused especially on the recent findings in the transcriptional regulation of PRCs, the oncogenic and tumor-suppressive roles of PcG proteins, and the research progress of inhibitors targeting PRCs.
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Xu L, Zhang J, Sun J, Hou K, Yang C, Guo Y, Liu X, Kalvakolanu DV, Zhang L, Guo B. Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers. Biochem Pharmacol 2022; 202:115110. [PMID: 35640714 DOI: 10.1016/j.bcp.2022.115110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/05/2023]
Abstract
The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.
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Affiliation(s)
- Libo Xu
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jinghua Zhang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jicheng Sun
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Kunlin Hou
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Chenxin Yang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Ying Guo
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Xiaorui Liu
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Dhan V Kalvakolanu
- Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Maryland School Medicine, Baltimore, MD, USA
| | - Ling Zhang
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China.
| | - Baofeng Guo
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China.
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23
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Van den Eynde C, Held K, Ciprietti M, De Clercq K, Kerselaers S, Marchand A, Chaltin P, Voets T, Vriens J. Loratadine, an antihistaminic drug, suppresses the proliferation of endometrial stromal cells by inhibition of TRPV2. Eur J Pharmacol 2022; 928:175086. [PMID: 35714693 DOI: 10.1016/j.ejphar.2022.175086] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 11/03/2022]
Abstract
The transient receptor potential (TRP) channel TRPV2 is widely expressed in a variety of different cell types and tissues. However, elucidating the exact biological functions of TRPV2 is significantly hampered by the lack of selective pharmacological tools to modulate channel activity in vitro and in vivo. This study aimed to identify new compounds that modify TRPV2 activity via the use of a plate-based calcium imaging approach to screen a drug repurposing library. Three antihistaminic drugs, loratadine, astemizole and clemizole were identified to reduce calcium-influx evoked by the TRPV2 agonist tetrahydrocannabivarin in HEK293 cells expressing murine TRPV2. Using single-cell calcium-microfluorimetry and whole-cell patch clamp recordings, we further confirmed that all three compounds induced a concentration-dependent block of TRPV2-mediated Ca2+ influx and whole-cell currents, with loratadine being the most potent antagonist of TRPV2. Moreover, this study demonstrated that loratadine was able to block both the human and mouse TRPV2 orthologs, without inhibiting the activity of other closely related members of the TRPV superfamily. Finally, loratadine inhibited TRPV2-dependent responses in a primary culture of mouse endometrial stromal cells and attenuated cell proliferation and migration in in vitro cell proliferation and wound healing assays. Taken together, our study revealed that the antihistaminic drugs loratadine, astemizole and clemizole target TRPV2 in a concentration-dependent manner. The identification of these antihistaminic drugs as blockers of TRPV2 may form a new starting point for the synthesis of more potent and selective TRPV2 antagonists, which could further lead to the unravelling of the physiological role of the channel.
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Affiliation(s)
- Charlotte Van den Eynde
- Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 box 611, 3000, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain & Disease Research, Herestraat 49 box 802, 3000, Leuven, Belgium
| | - Katharina Held
- Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 box 611, 3000, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain & Disease Research, Herestraat 49 box 802, 3000, Leuven, Belgium
| | - Martina Ciprietti
- Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 box 611, 3000, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain & Disease Research, Herestraat 49 box 802, 3000, Leuven, Belgium
| | - Katrien De Clercq
- Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 box 611, 3000, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain & Disease Research, Herestraat 49 box 802, 3000, Leuven, Belgium
| | - Sara Kerselaers
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain & Disease Research, Herestraat 49 box 802, 3000, Leuven, Belgium
| | - Arnaud Marchand
- CISTIM Leuven vzw, Gaston Geenslaan 2, 3001, Leuven, Heverlee, Belgium
| | - Patrick Chaltin
- CISTIM Leuven vzw, Gaston Geenslaan 2, 3001, Leuven, Heverlee, Belgium; Centre for Drug Design and Discovery (CD3), KU Leuven, Gaston Geenslaan 2, 3001, Leuven, Heverlee, Belgium
| | - Thomas Voets
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain & Disease Research, Herestraat 49 box 802, 3000, Leuven, Belgium
| | - Joris Vriens
- Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 box 611, 3000, Leuven, Belgium.
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24
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Wang B, Zhou MJ, Zhou QL. Visible-Light-Induced α,γ-C(sp 3)-H Difunctionalization of Piperidines. Org Lett 2022; 24:2894-2898. [PMID: 35416677 DOI: 10.1021/acs.orglett.2c00831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Herein, we describe a novel protocol for visible-light-induced α,γ-C(sp3)-H difunctionalization of piperidines. This redox-neutral, atom-economical protocol, which exhibits a broad substrate scope and good functional group compatibility, constitutes a concise, practical method for constructing piperidine-containing bridged-ring molecules. Preliminary mechanistic studies indicated that highly regioselective activation of the inert γ-C(sp3)-H bond of piperidines was achieved through a 1,5-hydrogen atom transfer reaction of a nitrogen radical generated in situ.
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Affiliation(s)
- Biao Wang
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Min-Jie Zhou
- Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
| | - Qi-Lin Zhou
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.,Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, China
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25
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Recent progress on small molecules targeting epigenetic complexes. Curr Opin Chem Biol 2022; 67:102130. [DOI: 10.1016/j.cbpa.2022.102130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/13/2022] [Accepted: 01/26/2022] [Indexed: 12/16/2022]
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26
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Zeng J, Zhang J, Sun Y, Wang J, Ren C, Banerjee S, Ouyang L, Wang Y. Targeting EZH2 for cancer therapy: From current progress to novel strategies. Eur J Med Chem 2022; 238:114419. [DOI: 10.1016/j.ejmech.2022.114419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/19/2022] [Accepted: 04/26/2022] [Indexed: 12/14/2022]
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27
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Identification of SET/EED dual binders as innovative PRC2 inhibitors. Future Med Chem 2022; 14:609-621. [DOI: 10.4155/fmc-2022-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: The inhibition of PRC2, implicated in the pathogenesis of several tumors, can be a useful therapeutic strategy for cancer treatment. In the literature, two types of PRC2 modulators are reported: competitive inhibitors of S-adenosyl methionine binding to the catalytic subunit EZH2; and allosteric ligands that prevent the interaction of the trimethylated H3K27 lysine in histone 3 to the EED subunit. The lack of dual EZH2/EED modulators drove us to search for compounds capable of recognizing both domains. Materials & methods: This goal was pursued by combining pharmacophore- and docking-based virtual screening of the Multi-Target Ligand Chemotheca database. Prediction tools for absorption, distribution, metabolism and excretion and pan-assay interference compounds were also applied. Results: Finally, five 1,2,3-triazole derivatives were identified as promising dual EZH2/EED modulators. Conclusion: Our multistage screening protocol highlighted the great potential of Chemotheca for identifying polypharmacological agents.
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28
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Link between the EZH2 noncanonical pathway and microtubule organization center polarization during early T lymphopoiesis. Sci Rep 2022; 12:3655. [PMID: 35256668 PMCID: PMC8901749 DOI: 10.1038/s41598-022-07684-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 02/22/2022] [Indexed: 12/11/2022] Open
Abstract
EZH2 plays an essential role at the β-selection checkpoint of T lymphopoiesis by regulating histone H3 lysine 27 trimethylation (H3K27me3) via its canonical mode of action. Increasing data suggest that EZH2 could also regulate other cellular functions, such as cytoskeletal reorganization, via its noncanonical pathway. Consequently, we investigated whether the EZH2 noncanonical pathway could be involved in early T-cell maturation, which requires cell polarization. We observed that EZH2 localization is tightly regulated during the early stages of T-cell development and that EZH2 relocalizes in the nucleus of double-negative thymocytes enduring TCRβ recombination and β-selection processes. Furthermore, we observed that EZH2 and EED, but not Suz12, colocalize with the microtubule organization center (MTOC), which might prevent its inappropriate polarization in double negative cells. In accordance with these results, we evidenced the existence of direct or indirect interaction between EED and α-tubulin. Taken together, these results suggest that the EZH2 noncanonical pathway, in association with EED, is involved in the early stages of T-cell maturation.
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29
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Mirzaei S, Gholami MH, Hushmandi K, Hashemi F, Zabolian A, Canadas I, Zarrabi A, Nabavi N, Aref AR, Crea F, Wang Y, Ashrafizadeh M, Kumar AP. The long and short non-coding RNAs modulating EZH2 signaling in cancer. J Hematol Oncol 2022; 15:18. [PMID: 35236381 PMCID: PMC8892735 DOI: 10.1186/s13045-022-01235-1] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology and Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, 1417466191, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Israel Canadas
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Translational Sciences, Xsphera Biosciences Inc., Boston, MA, USA
| | - Francesco Crea
- Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
| | - Yuzhuo Wang
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada.
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, 34956, Turkey.
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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30
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Zhang Q, Yang H, Feng Q, Cao J, Zhang Y, Li L, Yu L. Focus on the classical and non-classical functions of EZH2: Guide the development of inhibitors and degraders. Pharmacol Res 2022; 178:106159. [DOI: 10.1016/j.phrs.2022.106159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/16/2022]
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31
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Levy S, Somasundaram L, Raj IX, Ic-Mex D, Phal A, Schmidt S, Ng WI, Mar D, Decarreau J, Moss N, Alghadeer A, Honkanen H, Sarthy J, Vitanza N, Hawkins RD, Mathieu J, Wang Y, Baker D, Bomsztyk K, Ruohola-Baker H. dCas9 fusion to computer-designed PRC2 inhibitor reveals functional TATA box in distal promoter region. Cell Rep 2022; 38:110457. [PMID: 35235780 PMCID: PMC8984963 DOI: 10.1016/j.celrep.2022.110457] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 11/23/2021] [Accepted: 02/08/2022] [Indexed: 11/18/2022] Open
Abstract
Bifurcation of cellular fates, a critical process in development, requires histone 3 lysine 27 methylation (H3K27me3) marks propagated by the polycomb repressive complex 2 (PRC2). However, precise chromatin loci of functional H3K27me3 marks are not yet known. Here, we identify critical PRC2 functional sites at high resolution. We fused a computationally designed protein, EED binder (EB), which competes with EZH2 and thereby inhibits PRC2 function, to dCas9 (EBdCas9) to allow for PRC2 inhibition at a precise locus using gRNA. Targeting EBdCas9 to four different genes (TBX18, p16, CDX2, and GATA3) results in precise H3K27me3 and EZH2 reduction, gene activation, and functional outcomes in the cell cycle (p16) or trophoblast transdifferentiation (CDX2 and GATA3). In the case of TBX18, we identify a PRC2-controlled, functional TATA box >500 bp upstream of the TBX18 transcription start site (TSS) using EBdCas9. Deletion of this TATA box eliminates EBdCas9-dependent TATA binding protein (TBP) recruitment and transcriptional activation. EBdCas9 technology may provide a broadly applicable tool for epigenomic control of gene regulation.
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Affiliation(s)
- Shiri Levy
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Logeshwaran Somasundaram
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Infencia Xavier Raj
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Diego Ic-Mex
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Ashish Phal
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, School of Medicine, Seattle, WA 98105, USA
| | - Sven Schmidt
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Weng I Ng
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Daniel Mar
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA 98195, USA
| | - Justin Decarreau
- Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
| | - Nicholas Moss
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Division of Medical Genetics, Department of Medicine, University of Washington, School of Medicine, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ammar Alghadeer
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Oral Health Sciences, University of Washington, School of Dentistry, Seattle, WA 98109, USA; Department of Biomedical Dental Sciences, Imam Abdulrahman Bin Faisal University, College of Dentistry, Dammam 31441, Saudi Arabia
| | - Henrik Honkanen
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Jay Sarthy
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Cancer and Blood Disorder Center, Seattle Children's Hospital, Seattle, WA 98105, USA
| | - Nicholas Vitanza
- The Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - R David Hawkins
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Division of Medical Genetics, Department of Medicine, University of Washington, School of Medicine, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Julie Mathieu
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA
| | - Yuliang Wang
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA
| | - David Baker
- Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
| | - Karol Bomsztyk
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA 98195, USA
| | - Hannele Ruohola-Baker
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, School of Medicine, Seattle, WA 98105, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Oral Health Sciences, University of Washington, School of Dentistry, Seattle, WA 98109, USA.
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32
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Zhao Y, Guan YY, Zhao F, Yu T, Zhang SJ, Zhang YZ, Duan YC, Zhou XL. Recent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs. Eur J Med Chem 2022; 231:114144. [DOI: 10.1016/j.ejmech.2022.114144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/27/2021] [Accepted: 01/17/2022] [Indexed: 11/26/2022]
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Liu KL, Zhu K, Zhang H. An overview of the development of EED inhibitors to disable the PRC2 function. RSC Med Chem 2022; 13:39-53. [PMID: 35224495 PMCID: PMC8792826 DOI: 10.1039/d1md00274k] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 10/21/2021] [Indexed: 10/24/2023] Open
Abstract
Polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor suppressor genes and the blocking of transcripts related to immunity and cell terminal differentiation. Aberrations of PRC2 components, such as mutation and overexpression, have been observed in various cancers, which makes PRC2 a potential therapeutic target for cancer. Up to now, targeting the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represents the main strategy in the development of PRC2 inhibitors. Although significant progress has been made, new problems also emerge, e.g. the drug resistance caused by secondary mutations. In recent years, more and more efforts have shifted to another new strategy - targeting embryonic ectoderm development (EED) to disrupt its major interactions with other components, which are necessary to the PRC2 function, and some promising results have been obtained. This review summarizes the recent development of EED inhibitors as possible chemotherapy for cancer treatment, which could help accelerate future related research work.
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Affiliation(s)
- Kai-Lu Liu
- School of Biological Science and Technology, University of Jinan Jinan 250022 China
| | - Kongkai Zhu
- School of Biological Science and Technology, University of Jinan Jinan 250022 China
| | - Hua Zhang
- School of Biological Science and Technology, University of Jinan Jinan 250022 China
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34
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Conery AR, Rocnik JL, Trojer P. Small molecule targeting of chromatin writers in cancer. Nat Chem Biol 2021; 18:124-133. [PMID: 34952934 DOI: 10.1038/s41589-021-00920-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 10/13/2021] [Indexed: 01/10/2023]
Abstract
More than a decade after the launch of DNA methyltransferase and histone deacetylase inhibitors for the treatment of cancer, 2020 heralded the approval of the first histone methyltransferase inhibitor, revitalizing the concept that targeted manipulation of the chromatin regulatory landscape can have profound therapeutic impact. Three chromatin regulatory pathways-DNA methylation, histone acetylation and methylation-are frequently implicated in human cancer but hundreds of potentially druggable mechanisms complicate identification of key targets for therapeutic intervention. In addition to human genetics and functional screening, chemical biology approaches have proven critical for the discovery of key nodes in these pathways and in an ever-increasing complexity of molecularly defined human cancer contexts. This review introduces small molecule targeting approaches, showcases chemical probes and drug candidates for epigenetic writer enzymes, illustrates molecular features that may represent epigenetic dependencies and suggests translational strategies to maximize their impact in cancer therapy.
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35
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Wang S, C Ordonez-Rubiano S, Dhiman A, Jiao G, Strohmier BP, Krusemark CJ, Dykhuizen EC. Polycomb group proteins in cancer: multifaceted functions and strategies for modulation. NAR Cancer 2021; 3:zcab039. [PMID: 34617019 PMCID: PMC8489530 DOI: 10.1093/narcan/zcab039] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/12/2022] Open
Abstract
Polycomb repressive complexes (PRCs) are a heterogenous collection of dozens, if not hundreds, of protein complexes composed of various combinations of subunits. PRCs are transcriptional repressors important for cell-type specificity during development, and as such, are commonly mis-regulated in cancer. PRCs are broadly characterized as PRC1 with histone ubiquitin ligase activity, or PRC2 with histone methyltransferase activity; however, the mechanism by which individual PRCs, particularly the highly diverse set of PRC1s, alter gene expression has not always been clear. Here we review the current understanding of how PRCs act, both individually and together, to establish and maintain gene repression, the biochemical contribution of individual PRC subunits, the mis-regulation of PRC function in different cancers, and the current strategies for modulating PRC activity. Increased mechanistic understanding of PRC function, as well as cancer-specific roles for individual PRC subunits, will uncover better targets and strategies for cancer therapies.
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Affiliation(s)
- Sijie Wang
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Sandra C Ordonez-Rubiano
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Alisha Dhiman
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Guanming Jiao
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Brayden P Strohmier
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Casey J Krusemark
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Emily C Dykhuizen
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
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36
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Zoroddu S, Marchesi I, Bagella L. PRC2: an epigenetic multiprotein complex with a key role in the development of rhabdomyosarcoma carcinogenesis. Clin Epigenetics 2021; 13:156. [PMID: 34372908 PMCID: PMC8351429 DOI: 10.1186/s13148-021-01147-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/02/2021] [Indexed: 02/02/2023] Open
Abstract
Skeletal muscle formation represents a complex of highly organized and specialized systems that are still not fully understood. Epigenetic systems underline embryonic development, maintenance of stemness, and progression of differentiation. Polycomb group proteins play the role of gene silencing of stemness markers that regulate muscle differentiation. Enhancer of Zeste EZH2 is the catalytic subunit of the complex that is able to trimethylate lysine 27 of histone H3 and induce silencing of the involved genes. In embryonal Rhabdomyosarcoma and several other tumors, EZH2 is often deregulated and, in some cases, is associated with tumor malignancy. This review explores the molecular processes underlying the failure of muscle differentiation with a focus on the PRC2 complex. These considerations could open new studies aimed at the development of new cutting-edge therapeutic strategies in the onset of Rhabdomyosarcoma.
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Affiliation(s)
- Stefano Zoroddu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100, Sassari, Italy
| | - Irene Marchesi
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100, Sassari, Italy
- Kitos Biotech Srls, Tramariglio, Alghero, SS, Italy
| | - Luigi Bagella
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100, Sassari, Italy.
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
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37
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Tomassi S, Romanelli A, Zwergel C, Valente S, Mai A. Polycomb Repressive Complex 2 Modulation through the Development of EZH2-EED Interaction Inhibitors and EED Binders. J Med Chem 2021; 64:11774-11797. [PMID: 34351144 PMCID: PMC8404197 DOI: 10.1021/acs.jmedchem.1c00226] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
![]()
Epigenetics is nowadays
a well-accepted area of research. In the
last years, tremendous progress was made regarding molecules targeting
EZH2, directly or indirectly. Recently tazemetostat hit the market
after FDA-approval for the treatment of lymphoma. However, the impairment
of EZH2 activity by orthosteric intervention has proven to be effective
only in a limited subset of cancers. Considering the multiproteic
nature of the PRC2 complex and the marked dependence of EZH2 functions
on the other core subunits such as EED, in recent years, a new targeting
approach ascended to prominence. The possibility to cripple the function
of the PRC2 complex by interfering with its multimeric integrity fueled
the interest in developing EZH2–EED protein–protein
interaction and EED inhibitors as indirect modulators of PRC2-dependent
methyltransferase activity. In this Perspective, we aim to summarize
the latest findings regarding the development and the biological activity
of these emerging classes of PRC2 modulators from a medicinal chemist’s
viewpoint.
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Affiliation(s)
- Stefano Tomassi
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, 80131 Naples, Italy
| | - Annalisa Romanelli
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy
| | - Clemens Zwergel
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy
| | - Sergio Valente
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy
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38
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Du D, Xu D, Zhu L, Stazi G, Zwergel C, Liu Y, Luo Z, Li Y, Zhang Y, Zhu K, Ding Y, Liu J, Fan S, Zhao K, Zhang N, Kong X, Jiang H, Chen K, Zhao K, Valente S, Min J, Duan W, Luo C. Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction. J Med Chem 2021; 64:8194-8207. [PMID: 34077206 DOI: 10.1021/acs.jmedchem.0c02261] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinity Kd of 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
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Affiliation(s)
- Daohai Du
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.,Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Dandan Xu
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Licheng Zhu
- Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto M5G1L7 Ontario, Canada.,Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.,School of Life Sciences, Jinggangshan University, Ji'an 343009 Jiangxi, China
| | - Giulia Stazi
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome 00185, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome 00185, Italy
| | - Yanli Liu
- Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto M5G1L7 Ontario, Canada.,Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.,College of Pharmaceutical Sciences, Soochow University, Suzhou 215123 Jiangsu, China
| | - Zhongyuan Luo
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.,Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Yuanqing Li
- Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuanyuan Zhang
- Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Kongkai Zhu
- School of Biological Science and Technology, University of Jinan; Jinan 250022, China
| | - Yiluan Ding
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jingqiu Liu
- Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Shijie Fan
- Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Kaiyan Zhao
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Naixia Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiangqian Kong
- Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Hualiang Jiang
- Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Kaixian Chen
- Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China
| | - Kehao Zhao
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome 00185, Italy
| | - Jinrong Min
- Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto M5G1L7 Ontario, Canada.,Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China
| | - Wenhu Duan
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Cheng Luo
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.,Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China.,University of Chinese Academy of Sciences, Beijing 100049, China.,School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.,School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
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39
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Li X, Gera L, Zhang S, Chen Y, Lou L, Wilson LM, Xie ZR, Sautto G, Liu D, Danaher A, Mamouni K, Yang Y, Du Y, Fu H, Kucuk O, Osunkoya AO, Zhou J, Wu D. Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer. Theranostics 2021; 11:6873-6890. [PMID: 34093859 PMCID: PMC8171087 DOI: 10.7150/thno.49235] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 04/22/2021] [Indexed: 12/25/2022] Open
Abstract
Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.
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Affiliation(s)
- Xin Li
- Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA
- Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Lajos Gera
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA
| | - Shumin Zhang
- Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Yanhua Chen
- Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Lou
- School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Lauren Marie Wilson
- School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Zhong-Ru Xie
- School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Giuseppe Sautto
- Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
| | | | - Alira Danaher
- Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA
| | - Kenza Mamouni
- Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Yang Yang
- Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhong Du
- Department of Pharmacology and Chemical Biology, and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Haian Fu
- Department of Pharmacology and Chemical Biology, and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Omer Kucuk
- Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Adeboye O. Osunkoya
- Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- Departments of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Daqing Wu
- Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA
- Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- MetCure Therapeutics LLC, Atlanta, GA, USA
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40
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Davidovich C, Zhang Q. Allosteric regulation of histone lysine methyltransferases: from context-specific regulation to selective drugs. Biochem Soc Trans 2021; 49:591-607. [PMID: 33769454 PMCID: PMC8106495 DOI: 10.1042/bst20200238] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Histone lysine methyltransferases (HKMTs) are key regulators of many cellular processes. By definition, HKMTs catalyse the methylation of lysine residues in histone proteins. The enzymatic activities of HKMTs are under precise control, with their allosteric regulation emerging as a prevalent paradigm. We review the molecular mechanisms of allosteric regulation of HKMTs using well-studied histone H3 (K4, K9, K27 and K36) methyltransferases as examples. We discuss the current advances and future potential in targeting allosteric sites of HKMTs for drug development.
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Affiliation(s)
- Chen Davidovich
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- EMBL-Australia and the ARC Centre of Excellence in Advanced Molecular Imaging, Clayton, Victoria, Australia
| | - Qi Zhang
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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41
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Identification of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method. J Comput Aided Mol Des 2021; 35:601-611. [PMID: 33635506 DOI: 10.1007/s10822-021-00378-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 02/11/2021] [Indexed: 12/27/2022]
Abstract
Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase that is overexpressed in many cancers. Numerous EZH2 inhibitors have been developed as anticancer agents, but recent studies have also focused on protein-protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2 as a novel drug discovery target. Because EED indirectly enhances EZH2 enzymatic activity, EED-EZH2 PPI inhibitors suppress the methyltransferase activity and inhibit cancer growth. By contrast to the numerous promising EZH2 inhibitors, there are a paucity of EED-EZH2 PPI inhibitors reported in the literature. Here, we aimed to discover novel EED-EZH2 PPI inhibitors by first identifying possible binders of EED using an in-house knowledge-based in silico fragment mapping method. Next, 3D pharmacophore models were constructed from the arrangement pattern of the potential binders mapped onto the EED surface. In all, 16 compounds were selected by 3D pharmacophore-based virtual screening followed by docking-based virtual screening. In vitro evaluation revealed that five of these compounds exhibited inhibitory activities. This study has provided structural insights into the discovery and the molecular design of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method.
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42
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Martin MC, Zeng G, Yu J, Schiltz GE. Small Molecule Approaches for Targeting the Polycomb Repressive Complex 2 (PRC2) in Cancer. J Med Chem 2020; 63:15344-15370. [PMID: 33283516 DOI: 10.1021/acs.jmedchem.0c01344] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The polycomb repressive complex 2 (PRC2) is composed of three core subunits, enhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12), along with a number of accessory proteins. It is the key enzymatic protein complex that catalyzes histone H3 lysine 27 (H3K27) methylation to mediate epigenetic silencing of target genes. PRC2 thus plays essential roles in maintaining embryonic stem cell identity and in controlling cellular differentiation. Studies in the past decade have reported frequent overexpression or mutation of PRC2 in various cancers including prostate cancer and lymphoma. Aberrant PRC2 function has been extensively studied and proven to contribute to a large number of abnormal cellular processes, including those that lead to uncontrolled proliferation and tumorigenesis. Significant efforts have recently been made to develop small molecules targeting PRC2 function for potential use as anticancer therapeutics. In this review, we describe recent approaches to identify and develop small molecules that target PRC2. These various strategies include the inhibition of the function of individual PRC2 core proteins, the disruption of PRC2 complex formation, and the degradation of its subunits.
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Affiliation(s)
- M Cynthia Martin
- Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, United States
| | - Guihua Zeng
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Jindan Yu
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.,Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Gary E Schiltz
- Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, United States.,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.,Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
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43
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Martin CJ, Moorehead RA. Polycomb repressor complex 2 function in breast cancer (Review). Int J Oncol 2020; 57:1085-1094. [PMID: 33491744 PMCID: PMC7549536 DOI: 10.3892/ijo.2020.5122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/07/2020] [Indexed: 11/24/2022] Open
Abstract
Epigenetic modifications are important contributors to the regulation of genes within the chromatin. The polycomb repressive complex 2 (PRC2) is a multi‑subunit protein complex that is involved in silencing gene expression through the trimethylation of lysine 27 at histone 3 (H3K27me3). The dysregulation of this modification has been associated with tumorigenicity through the increased repression of tumour suppressor genes via condensing DNA to reduce access to the transcription start site (TSS) within tumor suppressor gene promoters. In the present review, the core proteins of PRC2, as well as key accessory proteins, will be described. In addition, mechanisms controlling the recruitment of the PRC2 complex to H3K27 will be outlined. Finally, literature identifying the role of PRC2 in breast cancer proliferation, apoptosis and migration, including the potential roles of long non‑coding RNAs and the miR‑200 family will be summarized as will the potential use of the PRC2 complex as a therapeutic target.
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Affiliation(s)
- Courtney J. Martin
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada
| | - Roger A. Moorehead
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada
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44
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Li Q, Liu KY, Liu Q, Wang G, Jiang W, Meng Q, Yi Y, Yang Y, Wang R, Zhu S, Li C, Wu L, Zhao D, Yan L, Zhang L, Kim JS, Zu X, Kozielski AJ, Qian W, Chang JC, Patnaik A, Chen K, Cao Q. Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2. Mol Cancer Ther 2020; 19:2023-2033. [PMID: 32855270 PMCID: PMC7541747 DOI: 10.1158/1535-7163.mct-20-0250] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/21/2020] [Accepted: 08/05/2020] [Indexed: 12/17/2022]
Abstract
Enhancer of zester homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of polycomb repressive complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the current developed small-molecule inhibitors targeting EZH2 enzymatic activities could not inhibit the growth and progression of solid tumors. Here, we discovered an antihistamine drug, ebastine, as a novel EZH2 inhibitor by targeting EZH2 transcription and subsequently downregulating EZH2 protein level and H3K27 trimethylation in multiple cancer cell lines at concentrations below 10 μmol/L. The inhibition of EZH2 by ebastine further impaired the progression, migration, and invasiveness of these cancer cells. Overexpression of Ezh2 wild-type and its mutant, H689A (lacking methyltransferase activity), rescued the neoplastic properties of these cancer cells after ebastine treatment, suggesting that EZH2 targeted by ebastine is independent of its enzymatic function. Next-generation RNA-sequencing analysis also revealed that C4-2 cells treated with 8 μmol/L ebastine showed a gene profiling pattern similar to EZH2-knockdown C4-2 cells, which was distinctively different from cells treated with GSK126, an EZH2 enzyme inhibitor. In addition, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer and drug-resistant castration-resistant prostate cancer patient-derived xenograft mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.
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Affiliation(s)
- Qiaqia Li
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Kilia Y Liu
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Qipeng Liu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Guangyu Wang
- Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York
| | - Weihua Jiang
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Qingshu Meng
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Yang Yi
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Yongyong Yang
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Rui Wang
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Sen Zhu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York
| | - Chao Li
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Longxiang Wu
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Dongyu Zhao
- Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York
| | - Lin Yan
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Lili Zhang
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York
| | - Jung-Sun Kim
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
| | - Xiongbing Zu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | | | - Wei Qian
- Houston Methodist Cancer Center, Houston, Texas
| | | | - Akash Patnaik
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Kaifu Chen
- Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas.
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York
| | - Qi Cao
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas
- Houston Methodist Cancer Center, Houston, Texas
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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45
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Chen Y, Bi X, Zhang F, Sun Z, Xu P, Jiang H, Lu W, Lu T, Ding H, Zhang N, Jiang H, Chen K, Zhou B, Luo C. Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain. Bioorg Chem 2020; 101:103991. [PMID: 32559581 DOI: 10.1016/j.bioorg.2020.103991] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 12/23/2022]
Abstract
CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 μM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.
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Affiliation(s)
- Yu Chen
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Xiaoyang Bi
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Fengcai Zhang
- School of Pharmacy, Nanchang University, Nanchang 330006, China
| | - Zhongya Sun
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Life and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Pan Xu
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Hao Jiang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Wenchao Lu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Tian Lu
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Hong Ding
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Naixia Zhang
- Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Hualiang Jiang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Kaixian Chen
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China
| | - Bing Zhou
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Cheng Luo
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China.
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46
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Abstract
Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.
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Affiliation(s)
- Ran Duan
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wenfang Du
- Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
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47
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Chen Y, Jin J. The application of ubiquitin ligases in the PROTAC drug design. Acta Biochim Biophys Sin (Shanghai) 2020; 52:776-790. [PMID: 32506133 DOI: 10.1093/abbs/gmaa053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/13/2022] Open
Abstract
Protein ubiquitylation plays important roles in many biological activities. Protein ubiquitylation is a unique process that is mainly controlled by ubiquitin ligases. The ubiquitin-proteasome system (UPS) is the main process to degrade short-lived and unwanted proteins in eukaryotes. Many components in the UPS are attractive drug targets. Recent studies indicated that ubiquitin ligases can be employed as tools in proteolysis-targeting chimeras (PROTACs) for drug discovery. In this review article, we will discuss the recent progress of the application of ubiquitin ligases in the PROTAC drug design. We will also discuss advantages and existing problems of PROTACs. Moreover, we will propose a few principles for selecting ubiquitin ligases in PROTAC applications.
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Affiliation(s)
- Yilin Chen
- Life Science Institute, Zhejiang University, Hangzhou 310058, China
| | - Jianping Jin
- Life Science Institute, Zhejiang University, Hangzhou 310058, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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48
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Zhou Y, Du DH, Wang J, Cai XQ, Deng AX, Nosjean O, Boutin JA, Renard P, Yang DH, Luo C, Wang MW. Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns. Chem Biol Drug Des 2020; 96:1024-1051. [PMID: 32394628 DOI: 10.1111/cbdd.13702] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/21/2020] [Accepted: 04/26/2020] [Indexed: 12/19/2022]
Abstract
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) along with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12), which implements transcriptional repression mainly by depositing trimethylation marks at lysine 27 of histone H3 (H3K27me3). Its catalytic activity is closely correlated with the stability of PRC2, and somatic activating mutation of EZH2 Y641F within the catalytic SET domain drives tumor aggressiveness, drug resistance, and poor prognosis. Here, we report two high-throughput screening (HTS) campaigns targeting EZH2 Y641F and EZH2-EED interaction, respectively. For the EZH2 Y641F mutant, the HTS campaign involved a library of 250,000 compounds using a homogenous time-resolved fluorescence (HTRF) assay and identified 162 hits, while 60,160 compounds were screened against EZH2-EED interaction with a fluorescence polarization (FP) assay resulting in 97 hits. Among the 162 EZH2 Y641F inhibitors, 38 also suppressed EZH2-EED interaction and 80 showed inhibitory effects on the wide-type (WT) EZH2. Meanwhile, 10 of the 97 EZH2-EED interaction inhibitors were active against WT EZH2. These hit compounds provide useful tools for the development of novel PRC2-EZH2 inhibitors targeting its catalytic and non-catalytic activities.
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Affiliation(s)
- Yan Zhou
- The National Center for Drug Screening and The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Dao-Hai Du
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jia Wang
- The National Center for Drug Screening and The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Xiao-Qing Cai
- The National Center for Drug Screening and The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Alicia X Deng
- The National Center for Drug Screening and The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | | | | | | | - De-Hua Yang
- The National Center for Drug Screening and The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Cheng Luo
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Ming-Wei Wang
- The National Center for Drug Screening and The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China.,School of Basic Medical Sciences, Fudan University, Shanghai, China
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49
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Cartron PF, Cheray M, Bretaudeau L. Epigenetic protein complexes: the adequate candidates for the use of a new generation of epidrugs in personalized and precision medicine in cancer. Epigenomics 2020; 12:171-177. [DOI: 10.2217/epi-2019-0169] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Until recently, drug development in oncology was focused on treating most patients for a specific cancer type without taking in account the heterogeneity between these patients in term of response to treatment. Therefore, this type of broad treatment approach excludes the treatment of patient not responding to disease-specific common drugs. In this review, we focus on the different types of epigenetic drugs currently used as DNA methylation inhibitor agents and their limits in patient care due to their lack of specificity. We also highlight the emergence of a new type of epidrug with higher target specificity due to their original mechanism of action: the disruption of protein complexes involved in the epigenetic modifications.
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Affiliation(s)
- Pierre-François Cartron
- CRCINA, INSERM, Université de Nantes, Nantes, France
- Equipe Apoptose et Progression tumorale, LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain, France
- Niches & Epigenetics of Tumors’ Network, Cancéropôle Grand Ouest, Nantes, France
- EpiSAVMEN Consortium, Région Pays de la Loire, Nantes, France
- LabEX IGO, Université de Nantes, Nantes, France
| | - Mathilde Cheray
- Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm 17177, Sweden
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50
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Lu W, Wang J, Li Y, Tao H, Xiong H, Lian F, Gao J, Ma H, Lu T, Zhang D, Ye X, Ding H, Yue L, Zhang Y, Tang H, Zhang N, Yang Y, Jiang H, Chen K, Zhou B, Luo C. Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors. Eur J Med Chem 2019; 184:111767. [PMID: 31622854 DOI: 10.1016/j.ejmech.2019.111767] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 09/24/2019] [Accepted: 10/06/2019] [Indexed: 01/09/2023]
Abstract
Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ± 19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.
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Affiliation(s)
- Wenchao Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Jun Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Yong Li
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Hongru Tao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Huan Xiong
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Fulin Lian
- Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Jing Gao
- Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Hongna Ma
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Pharmacy, Guiyang University of Traditional Chinese Medicine, South Dong Qing Road, Guizhou, 550025, China
| | - Tian Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Dan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Key Laboratory of Guizhou for Fermentation Engineering and Biomedicine, School of Pharmaceutical Sciences, Guizhou University, Guizhou, 550025, China
| | - Xiaoqing Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; College of Life Sciences, Zhejiang Sci-Tech University, 928 No.2 Street, Hangzhou, 310018, China
| | - Hong Ding
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Liyan Yue
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Yuanyuan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Huanyu Tang
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Naixia Zhang
- Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Yaxi Yang
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Hualiang Jiang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Kaixian Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China
| | - Bing Zhou
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
| | - Cheng Luo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China.
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