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Journal of Experimental & Clinical Cancer Research
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Open Access 01-12-2024 | Breast Cancer | Research

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

Authors: Yaxun Guo, Yuzhan Li, Zhongmei Zhou, Lei Hou, Wenjing Liu, Wenlong Ren, Dazhao Mi, Jian Sun, Xueqin Dai, Yingying Wu, Zhuo Cheng, Tingyue Wu, Qianmei Luo, Cong Tian, Fubing Li, Zhigang Yu, Yihua Chen, Ceshi Chen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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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.
Appendix
Available only for authorised users
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Metadata
Title
Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer
Authors
Yaxun Guo
Yuzhan Li
Zhongmei Zhou
Lei Hou
Wenjing Liu
Wenlong Ren
Dazhao Mi
Jian Sun
Xueqin Dai
Yingying Wu
Zhuo Cheng
Tingyue Wu
Qianmei Luo
Cong Tian
Fubing Li
Zhigang Yu
Yihua Chen
Ceshi Chen
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-024-03237-y

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