2. Academic Validation
  3. Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer

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

  • J Exp Clin Cancer Res. 2024 Nov 30;43(1):314. doi: 10.1186/s13046-024-03237-y.
Yaxun Guo # 1,  Yuzhan Li # 2,  Zhongmei Zhou 3,  Lei Hou 4,  Wenjing Liu 5,  Wenlong Ren 6 7,  Dazhao Mi 2,  Jian Sun 5,  Xueqin Dai 8,  Yingying Wu 9,  Zhuo Cheng 7,  Tingyue Wu 7,  Qianmei Luo 7,  Cong Tian 4,  Fubing Li 10,  Zhigang Yu 11 12 13,  Yihua Chen 14 15 16,  Ceshi Chen 17 18
Affiliations

Affiliations

  • 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 Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China. mtlfb0408@163.com.
  • 11 Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, 250033, China. yuzhigang@sdu.edu.cn.
  • 12 Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, 250033, China. yuzhigang@sdu.edu.cn.
  • 13 Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan, 250033, China. yuzhigang@sdu.edu.cn.
  • 14 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. chenyihua@kmmu.edu.cn.
  • 15 School of Pharmaceutical Sciences, Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, China. chenyihua@kmmu.edu.cn.
  • 16 Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, 650500, China. chenyihua@kmmu.edu.cn.
  • 17 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. chenc@kmmu.edu.cn.
  • 18 Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China. chenc@kmmu.edu.cn.
  • # Contributed equally.
PMID: 39614393 DOI: 10.1186/s13046-024-03237-y
Abstract

Background: 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.

Methods: This study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo.

Results: 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.

Conclusions: These findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC.

Trial registration: Ethics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023.

Keywords

KLF5; PRMT5; PROTAC; TNBC.

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