Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Less studied than the other protein arginine methyltransferase
isoforms, PRMT7 and PRMT9 have recently been identified as important
therapeutic targets. Yet, most of their biological roles and functions
are still to be defined, as well as the structural requirements that
could drive the identification of selective modulators of their activity.
We recently described the structural requirements that led to the
identification of potent and selective PRMT4 inhibitors spanning both
the substrate and the cosubstrate pockets. The reanalysis of the data
suggested a PRMT7 preferential binding for shorter derivatives and
prompted us to extend these structural studies to PRMT9. Here, we
report the identification of the first potent PRMT7/9 inhibitor and
its binding mode to the two PRMT enzymes. Label-free quantification
mass spectrometry confirmed significant inhibition of PRMT activity
in cells. We also report the setup of an effective AlphaLISA assay
to screen small molecule inhibitors of PRMT9.