Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection. [Display omitted] •GSK3368715 is a potent inhibitor of type I protein arginine methyltransferases•GSK3368715 alters exon usage and has activity against multiple cancer models•GSK3368715 synergizes with the PRMT5 inhibitor GSK3326595 to inhibit tumor growth•MTAP gene deficiency impairs PRMT5 activity, sensitizing cancer cells to GSK3368715 Fedoriw et al. show that the type I protein arginine methyltransferases (PRMT) inhibitor GSK3368715 has strong anti-cancer activity and synergizes with PRMT5 inhibition. MTAP deficiency causes accumulation of an endogenous PRMT5 inhibitor, suggesting MTAP status as a predictive biomarker for GSK3368715.