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Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer
Yaxun Guo1, Yuzhan Li2, Zhongmei Zhou3
1Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, 250033, China.
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.
Insights
A novel PROTAC degrader, YZ-836P, effectively targets PRMT5 in triple-negative breast cancer (TNBC). This compound shows superior efficacy in preclinical models, offering a promising new therapeutic avenue for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective therapies.
- PRMT5 is upregulated in TNBC and represents a key therapeutic target.
- Proteolysis Targeting Chimeras (PROTAC) offer a novel approach to protein degradation.
Purpose of the Study:
- To develop and evaluate PRMT5-targeting PROTAC degraders for TNBC treatment.
- To assess the in vitro and in vivo efficacy of novel compounds against TNBC.
Main Methods:
- Design, synthesis, and screening of PRMT5-targeting PROTAC compounds.
- In vitro assays to evaluate cytotoxicity, cell cycle arrest, and apoptosis induction.
- In vivo studies using patient-derived organoids and xenograft models.
Main Results:
- YZ-836P demonstrated potent cytotoxic effects and reduced PRMT5 and KLF5 protein levels in TNBC cells.
- YZ-836P induced G1 cell cycle arrest and apoptosis, superior to previously reported PRMT5 PROTACs.
- The compound promoted PRMT5 ubiquitination and degradation via a CRBN-dependent mechanism.
- YZ-836P effectively inhibited TNBC growth in patient-derived organoids and xenografts.
Conclusions:
- YZ-836P is a highly effective PRMT5 degrader with significant therapeutic potential for TNBC.
- These findings support the advancement of YZ-836P as a clinical candidate for TNBC treatment.
