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Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer

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机构： [1]Department of Breast Surgery, The Second Hospital of Shandong University, Jinan 250033, China [2]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China [3]The School of Continuing Education, Kunming Medical University, Kunming 650500, China [4]Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China [5]Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China [6]School of Life Science, University of Science & Technology of China, Hefei 230027, China [7]Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China [8]Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China [9]Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China [10]Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan 250033, China [11]Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan 250033, China [12]School of Pharmaceutical Sciences, Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China [13]Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming 650500, China

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关键词： PROTAC PRMT5 KLF5 TNBC

摘要：

Triple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation.This study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo.Through the design, synthesis and screening of a series of targeted compounds, we identified YZ-836P as an effective compound that exerted cytotoxic effects and reduced the protein levels of PRMT5 and its key downstream target protein KLF5 in TNBC after 48 h. Its efficacy was significantly superior to the PRMT5 PROTAC degraders that had been reported. YZ-836P induced G1 phase cell cycle arrest and significantly induced apoptosis in TNBC cells. Additionally, we demonstrated that YZ-836P promoted the ubiquitination and degradation of PRMT5 in a cereblon (CRBN)-dependent manner. Notably, YZ-836P exhibited pronounced efficacy in inhibiting the growth of TNBC patient-derived organoids and xenografts in nude mice.These findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC.Ethics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023.© 2024. The Author(s).

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大类 | 1 区

医学

小类 | 2 区肿瘤学

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最新[2023]版：

Q1 ONCOLOGY

影响因子： 11.4 最新[2023版] 11.4 最新五年平均 0 出版当年[2024版] 0 出版当年五年平均 11.4 出版前一年[2023版]

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第一作者机构： [1]Department of Breast Surgery, The Second Hospital of Shandong University, Jinan 250033, China

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通讯机构： [1]Department of Breast Surgery, The Second Hospital of Shandong University, Jinan 250033, China [2]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China [5]Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China [8]Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China [10]Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan 250033, China [11]Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan 250033, China [12]School of Pharmaceutical Sciences, Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China [13]Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming 650500, China

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Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer

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