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

Less studied than the other protein arginine methyltransferaseisoforms, PRMT7 and PRMT9 have recently been identified as importanttherapeutic targets. Yet, most of their biological roles and functionsare still to be defined, as well as the structural requirements thatcould drive the identification of selective modulators of their activity.We recently described the structural requirements that led to theidentification of potent and selective PRMT4 inhibitors spanning boththe substrate and the cosubstrate pockets. The reanalysis of the datasuggested a PRMT7 preferential binding for shorter derivatives andprompted us to extend these structural studies to PRMT9. Here, wereport the identification of the first potent PRMT7/9 inhibitor andits binding mode to the two PRMT enzymes. Label-free quantificationmass spectrometry confirmed significant inhibition of PRMT activityin cells. We also report the setup of an effective AlphaLISA assayto screen small molecule inhibitors of PRMT9