A dual inhibitor of PRMT5 and PRMT7
DS-437 is a dual inhibitor of protein arginine methyltransferase 5 (PRMT5) and PRMT7 (IC50s = 5.9 and 6 μM, respectively).[1] 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.[1],[2] 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.[2] 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.
Reference:
[1]. Smil, D., Eram, M.S., Li, F., et al. Discovery of a dual PRMT5-PRMT7 inhibitor. ACS Med. Chem. Lett. 6(4), 408-412 (2015).
[2]. Nagai, Y., Ji, M.Q., Zhu, F., et al. PRMT5 associates with the FOXP3 homomer and when disabled enhances targeted p185erbB2/neu tumor immunotherapy. Front. Immunol. 10:174, (2019).
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