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Updated: Dec 22, 2025
Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
Published on: August 7, 2021
Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor
Yudao Shen1, Fengling Li2, Magdalena M Szewczyk2
1Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Abstract:
Protein arginine methyltransferase 6 (PRMT6) plays important roles in several biological processes associated with multiple cancers. Well-characterized potent, selective, and cell-active PRMT6 inhibitors are invaluable tools for testing biological and therapeutic hypotheses. Although there are several known reversible PRMT6 inhibitors, covalent PRMT6 inhibitors have not been reported. Based on a cocrystal structure of PRMT6-MS023 (a type I PRMT inhibitor), we discovered the first potent and cell-active irreversible PRMT6 inhibitor, 4 (MS117). The covalent binding mode of compound 4 to PRMT6 was confirmed by mass spectrometry and kinetic studies and by a cocrystal structure. Compound 4 did not covalently modify other closely related PRMTs, potently inhibited PRMT6 in cells, and was selective for PRMT6 over other methyltransferases. We also developed two structurally similar control compounds, 5 (MS167) and 7 (MS168). We provide these valuable chemical tools to the scientific community for further studying PRMT6 physiological and pathophysiological functions.
Insights
Researchers developed the first potent, cell-active irreversible inhibitor for Protein Arginine Methyltransferase 6 (PRMT6). This new compound, MS117, provides a valuable tool for cancer research and understanding PRMT6 functions.
Area of Science:
- Biochemistry
- Chemical Biology
- Cancer Research
Background:
- Protein Arginine Methyltransferase 6 (PRMT6) is implicated in various cancer-related biological processes.
- Potent, selective, and cell-active PRMT6 inhibitors are crucial for investigating PRMT6's role in biology and therapy.
- Currently, only reversible PRMT6 inhibitors are known; irreversible inhibitors have not been reported.
Purpose of the Study:
- To discover and characterize the first potent and cell-active irreversible PRMT6 inhibitor.
- To provide novel chemical tools for studying PRMT6 in physiological and pathophysiological contexts.
Main Methods:
- Cocrystal structure analysis of PRMT6-MS023 to guide inhibitor design.
- Synthesis and characterization of compound 4 (MS117) as an irreversible PRMT6 inhibitor.
- Confirmation of covalent binding using mass spectrometry, kinetic studies, and cocrystal structure analysis.
- Evaluation of compound 4's selectivity against related PRMTs and other methyltransferases.
Main Results:
- Discovery of compound 4 (MS117), the first potent and cell-active irreversible PRMT6 inhibitor.
- Confirmation of MS117's covalent binding to PRMT6 through multiple experimental approaches.
- Demonstration of MS117's selectivity, showing no covalent modification of related PRMTs and potent inhibition of PRMT6 in cells.
- Development of structurally similar control compounds (MS167 and MS168).
Conclusions:
- Compound 4 (MS117) represents a significant advancement as the first irreversible PRMT6 inhibitor.
- MS117 is a potent, selective, and cell-active chemical tool for PRMT6 research.
- The developed inhibitors will facilitate further exploration of PRMT6's functions in cancer and other diseases.
