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

  • ACS Chem Biol. 2025 Jun 20;20(6):1333-1346. doi: 10.1021/acschembio.5c00160.
Zhihang Shen  1 ,  Xiaozhi Yang  1 ,  Gustavo Seabra  1 ,  Xueyong Xu  2 ,  Jiawei Dong  3 ,  Jason Orr Brant  4 ,  Wei Zhou  1 ,  Juan Guan  3 ,  Wen Jiang  2 ,  Chenglong Li  1
Affiliations
  • 1. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32611-7011, United States.
  • 2. Department of Biological Sciences, College of Medicine, Purdue University, West Lafayette, Indiana 47907, United States.
  • 3. Department of Chemical Biology & Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712-1139, United States.
  • 4. Department of Biostatistics, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, Florida 32611-7011, United States.
PMID: 40440106 DOI: 10.1021/acschembio.5c00160
Abstract

Protein arginine methyltransferase 5 (PRMT5), which uniquely binds to 5'-methylthioadenosine (MTA) among the PRMT family, is emerging as an attractive epigenetic target for 5'-methylthioadenosine Phosphorylase (MTAP)-deleted Cancer treatments. Here, we report the discovery of a novel inhibitor 16-19F, which is a potent binder to the PRMT5•MTA, PRMT5•SAH, and PRMT5•SAM complexes and selectively inhibited MTAP-deleted Cancer cell growth. Based on transcriptome analysis, we found that kinetochore metaphase signaling and cell cycle control of the chromosomal replication pathway were downregulated after 16-19F treatment in the MDA-MB-231 TNBC cell line. Additionally, we identified a new PRMT5 substrate, MCM7, an important component of DNA helicase, and figured out the potential methylation site Arg219 by site-directed mutagenesis and computational analysis. Moreover, we showed that 16-19F treatment regulated MCM7 localization, which is involved through liquid-liquid phase separation mechanisms, including the formation of stress granules. Together, we discovered a potential novel drug candidate and revealed an unknown mechanism in which PRMT5 methylation altered MCM7 localization by modulating stress granule formation.

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