DS-437 is a dual inhibitor of protein arginine methyltransferase 5 (PRMT5) and PRMT7 (IC50s = 5.9 and 6 μM, respectively). It is selective for PRMT5 and PRMT7 over a panel of 29 additional protein, DNA, and RNA methyltransferases at 50 μM, but also inhibits DNMT3A and DNMT3B (IC50s = 52 and 62 μM, respectively). DS-437 (2.5 and 10 μM) inhibits symmetrical arginine dimethylation of FOXP3 in HEK293T cells, as well as symmetrical arginine dimethylation of p60 and the ribonucleoproteins SmD1/D3 and SmB/B’ in MDA-MB-231 cells in a concentration-dependent manner. It inhibits the ability of regulatory T cells (Tregs) to suppress effector T cell (Teff) proliferation in vitro in human and murine Treg suppression assays. DS-437 (10 mg/kg five times per week) reduces tumor growth in a CT26Her2 murine colon cancer model when administered in combination with the anti-p185erbB2/neu antibody 4D5.
