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Updated: Sep 10, 2025
08:11
Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
Published on: August 7, 2021
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PRMT5: A Promising Synthetical Lethal Target for MTAP-Deleted Cancers
Bang Li1, Jin-Qi Yu1, Zhenjiao Yang1
1Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Journal of Medicinal Chemistry
|August 22, 2025
Summary
Second-generation PRMT5 inhibitors offer a precision oncology approach by selectively targeting cancer cells with MTAP deletions. This strategy overcomes the hematological toxicities seen with earlier PRMT5 inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Protein arginine methyltransferase 5 (PRMT5) is a key target in cancer therapy.
- First-generation PRMT5 inhibitors caused dose-limiting hematological toxicities due to non-selective inhibition.
- PRMT5 is essential for normal hematopoiesis, complicating therapeutic strategies.
Purpose of the Study:
- To analyze binding modes of PRMT5 complexes.
- To highlight the development of second-generation MTA-cooperative PRMT5 inhibitors.
- To discuss challenges and opportunities for future PRMT5 inhibitor drug development.
Main Methods:
- Analysis of binding modes between PRMT5·MTA and PRMT5·SAM complexes.
- Utilizing cocrystal structures of PRMT5·MTA complexes.
- Review of synthetic lethal inhibitor strategies.
Main Results:
- Second-generation inhibitors selectively target PRMT5 in MTAP-deleted cancer cells.
- These inhibitors preserve PRMT5 function in MTAP-wildtype cells, reducing toxicity.
- Cocrystal structures guided the discovery of improved MTA-cooperative inhibitors.
Conclusions:
- MTA-cooperative PRMT5 inhibitors represent a promising precision oncology strategy.
- Selective inhibition overcomes toxicity issues of earlier PRMT5-targeted therapies.
- Further development holds potential for effective cancer treatment.
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