2. Academic Validation
  3. Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader

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

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.

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