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

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.