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A review of the known MTA-cooperative PRMT5 inhibitors

Mei Hu1, Xiang Chen1

  • 1Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University 1-1 Xiangling Road Luzhou Sichuan 646000 People's Republic of China 86487165@qq.com.

RSC Advances
|December 18, 2024
PubMed

Insights

Protein arginine methyltransferase 5 (PRMT5) inhibitors show promise as cancer therapies, but toxicity limits their use. This review examines PRMT5 inhibitor design, safety, and potential risks for clinical application.

Area of Science:

  • Oncology
  • Epigenetics
  • Medicinal Chemistry

Background:

  • Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic regulator implicated in various cancers.
  • Numerous PRMT5 inhibitors are in clinical trials, with second-generation drugs showing synthetic lethal potential.
  • Despite clinical interest, dose-limiting toxicities have prevented marketing approval for PRMT5 inhibitors.

Purpose of the Study:

  • To review the design strategies and structure-activity relationships (SAR) of methylthioadenosine (MTA)-cooperative PRMT5 inhibitors.
  • To analyze the clinical safety profiles of first- and second-generation PRMT5 inhibitors.
  • To discuss potential in vivo vulnerabilities and nitrosamine risks associated with PRMT5 inhibitor development.

Main Methods:

  • Literature review of PRMT5 inhibitors in cancer therapy.
  • Analysis of structure-activity relationships (SAR) for MTA-cooperative inhibitors.
  • Review of clinical safety data for representative PRMT5 inhibitors.

Main Results:

  • Second-generation PRMT5 inhibitors exhibit significant clinical application value based on synthetic lethality.
  • Inherent dose-limiting toxicities remain a challenge for PRMT5 inhibitor development.
  • Potential in vivo vulnerability of the aromatic amine moiety and nitrosamine formation risks are identified.

Conclusions:

  • PRMT5 is a promising synthetic lethal target for cancer therapy, akin to PARP inhibitors.
  • Addressing toxicity and potential manufacturing risks is crucial for clinical success.
  • Further research into PRMT5 inhibitor design and safety is warranted for therapeutic advancement.

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