Discovery and Mechanism of 16-19F, a Novel Synthetic Lethal Inhibitor of the PRMT5•MTA Complex in MTAP-Deleted Cancer

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Zhihang Shen1, Xiaozhi Yang1, Gustavo Seabra1

  • 1Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32611-7011, United States.

ACS Chemical Biology
|May 29, 2025
PubMed

Insights

A novel inhibitor, 16-19F, targets Protein Arginine Methyltransferase 5 (PRMT5) for cancers lacking MTAP. This drug candidate selectively inhibits cancer cell growth and reveals new insights into epigenetic regulation of MCM7 localization.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Pharmacology

Background:

  • Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic regulator.
  • PRMT5 is a potential therapeutic target in cancers with methylthioadenosine phosphorylase (MTAP) deletion.
  • PRMT5 uniquely binds 5'-methylthioadenosine (MTA).

Purpose of the Study:

  • To discover and characterize novel PRMT5 inhibitors for MTAP-deleted cancers.
  • To elucidate the mechanism of action of PRMT5 inhibition.
  • To identify new PRMT5 substrates and their roles in cancer.

Main Methods:

  • Inhibitor screening and characterization (16-19F).
  • Cell-based assays for cancer cell growth inhibition.
  • Transcriptome analysis (RNA-seq).
  • Biochemical assays (site-directed mutagenesis, computational analysis) to identify PRMT5 substrates and methylation sites.
  • Analysis of protein localization and stress granule formation.

Main Results:

  • A novel PRMT5 inhibitor, 16-19F, was discovered, potently binding PRMT5 complexes.
  • 16-19F selectively inhibited MTAP-deleted cancer cell growth.
  • Transcriptome analysis revealed downregulation of kinetochore metaphase signaling and cell cycle control pathways.
  • MCM7 was identified as a novel PRMT5 substrate, with Arg219 as a potential methylation site.
  • 16-19F treatment altered MCM7 localization via modulation of stress granule formation.

Conclusions:

  • 16-19F is a promising drug candidate for MTAP-deleted cancers.
  • PRMT5 inhibition affects key cancer pathways including cell cycle and DNA replication.
  • PRMT5-mediated methylation of MCM7 influences its localization and stress granule dynamics, representing a novel regulatory mechanism.

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