Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader

  • J Med Chem. 2025 Apr 24;68(8):8543-8563. doi: 10.1021/acs.jmedchem.5c00198.
Yue Zhong  1  2  3 ,  Huensuk Kim  1  2  3 ,  Chao Qian  1  2  3 ,  Ling Xie  4 ,  Xian Chen  4 ,  Yan Xiong  1  2  3 ,  Jacqueline Hu  1  2  3 ,  Matthew Chen  1  2  3 ,  Ernesto Guccione  2  3 ,  Yudao Shen  1  2  3 ,  Jian Jin  1  2  3
Affiliations
  • 1. Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 3. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 4. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 40232306 DOI: 10.1021/acs.jmedchem.5c00198
Abstract

Protein arginine methyltransferase 5 (PRMT5) plays crucial roles in the regulation of various biological processes through the mono- and symmetric dimethylation of protein substrates. PRMT5 is overexpressed in various human cancers and its overexpression is associated with poor prognosis. We previously reported the first-in-class PRMT5 Degrader, MS4322, which is also the only von Hippel-Lindau (VHL)-recruiting PRMT5 Degrader to date. Here, we performed structure-activity relationship (SAR) studies exploring various linkers and ligands of VHL and PRMT5, which resulted in the best-in-class PRMT5 Degrader, MS115 (compound 10). Compound 10 potently and selectively degraded PRMT5 and its coactivator, MEP50, in concentration-, time-, and ubiquitin-proteasome system-dependent manners. It displayed much improved PRMT5/MEP50 degradation potency over MS4322, which translated to better antiproliferative effect in both breast and prostate Cancer cells. Overall, we discovered a highly potent and selective PRMT5/MEP50 complex degrader, which is an invaluable chemical biology tool and a potential Cancer therapeutic.

Products