2. Academic Validation
  3. Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor

Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor

  • J Med Chem. 2020 May 28;63(10):5477-5487. doi: 10.1021/acs.jmedchem.0c00406.
Yudao Shen 1,  Fengling Li 2,  Magdalena M Szewczyk 2,  Levon Halabelian 2,  Kwang-Su Park 1,  Irene Chau 2,  Aiping Dong 2,  Hong Zeng 2,  He Chen 1,  Fanye Meng 1,  Dalia Barsyte-Lovejoy 2,  Cheryl H Arrowsmith 2 3,  Peter J Brown 2,  Jing Liu 1,  Masoud Vedadi 2 4,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount 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.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 3 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
  • 4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
PMID: 32367723 DOI: 10.1021/acs.jmedchem.0c00406
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.

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