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Updated: Sep 10, 2025

Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
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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
PubMed

Insights

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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