GSK3326595 (EPZ015938)

GSK3326595 is an inhibitor of protein arginine methyltransferase 5 (PRMT5).¹ It inhibits methylation of peptides derived from the PRMT5 substrates histone H4 and H2A, SmD3, FUBP1, and HNRNPH1 by the PRMT5/MEP50 complex with IC₅₀ values ranging from 5.9 to 19.7 nM and is more than 4,000-fold selective for PRMT5/MEP50 over a panel of 20 methyltransferases. GSK3326595 (200 nM) induces alternative splicing of MDM4 in Z-138, MCF-7, JM1, and DOHH-2 cells and increases p53 and p21 protein levels in Z-138 cells in a concentration-dependent manner. GSK3326595 inhibits growth and symmetric dimethyl arginine (SDMA) methylation in several lymphoma and breast cancer cell lines. It also reduces tumor growth in a Z-138 mouse xenograft model when administered at doses of 25, 50, and 100 mg/kg twice per day.

1.Gerhart, S.V., Kellner, W.A., Thompson, C., et al.Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicingSci. Rep.8(1)9711(2018)