دورية أكاديمية
Design, synthesis, and evaluation of VHL-based EZH2 degraders for breast cancer.
| العنوان: | Design, synthesis, and evaluation of VHL-based EZH2 degraders for breast cancer. |
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| المؤلفون: | Xiao B; Department of Chemistry, Tsinghua University, Beijing 100084, China; The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China., Shi Z; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China., Liu J; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China., Huang Q; Department of Chemistry, Tsinghua University, Beijing 100084, China; The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China., Shu K; The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China., Liu F; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China., Zhi C; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China., Zhang D; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China., Wu L; The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China., Yang S; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China., Zeng X; The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China., Fan T; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. Electronic address: fantt@szbl.ac.cn., Liu Z; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, China; Shenzhen Winkey Technology Co., Ltd., Shenzhen 518000, China. Electronic address: liuzijian1115@163.com., Jiang Y; The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: jiangyy@sz.tsinghua.edu.cn. |
| المصدر: | Bioorganic chemistry [Bioorg Chem] 2024 Feb; Vol. 143, pp. 107078. Date of Electronic Publication: 2024 Jan 02. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| مواضيع طبية MeSH: | Breast Neoplasms*/drug therapy , Enhancer of Zeste Homolog 2 Protein*/drug effects , Enhancer of Zeste Homolog 2 Protein*/metabolism , Proteolysis Targeting Chimera*/chemistry , Proteolysis Targeting Chimera*/pharmacology, Female ; Humans ; Cell Line, Tumor ; Cell Proliferation ; Enzyme Inhibitors/pharmacology ; Von Hippel-Lindau Tumor Suppressor Protein/pharmacology |
| مستخلص: | EZH2 (enhancer of zeste homolog 2) is one of the most important histone methyltransferases (HMTs), and overexpression of EZH2 can lead to proliferation, migration and angiogenesis of tumor cells. But most of EZH2 inhibitors are only effective against some hematologic malignancies and have poor efficacy against solid tumors. Here, we report the design, synthesis, and evaluation of highly potent proteolysis targeting chimeric (PROTACs) small molecules targeting EZH2. We developed a potent and effective EZH2 degrader P4, which effectively induced EZH2 protein degradation and inhibited breast cancer cell growth. Further studies showed that P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023. Published by Elsevier Inc.) |
| فهرسة مساهمة: | Keywords: Anti-cancer; Breast cancer; Drug design; Enhancer of zeste homolog 2; Proteolysis targeting chimeras |
| المشرفين على المادة: | EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein) 0 (Enzyme Inhibitors) EC 2.1.1.43 (EZH2 protein, human) EC 6.3.2.- (VHL protein, human) EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein) 0 (Proteolysis Targeting Chimera) |
| تواريخ الأحداث: | Date Created: 20240105 Date Completed: 20240125 Latest Revision: 20240125 |
| رمز التحديث: | 20240126 |
| DOI: | 10.1016/j.bioorg.2023.107078 |
| PMID: | 38181661 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1090-2120 |
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| DOI: | 10.1016/j.bioorg.2023.107078 |