Home Blog of Signal Transduction Methylation PRMT Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

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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.

 

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The provided information describes the potential therapeutic approach of inhibiting type I protein arginine methyltransferases (PRMTs) for the treatment of human cancers. It introduces a specific inhibitor called GSK3368715 (EPZ019997), which is a potent and reversible type I PRMT inhibitor. This compound has demonstrated anti-tumor effects in various human cancer models.

Additionally, the report highlights the synergistic effects observed when combining GSK3368715 with the inhibition of PRMT5, the predominant type II PRMT. This combination leads to enhanced inhibition of cancer cell growth.

Furthermore, the report discusses the role of the methylthioadenosine phosphorylase gene (MTAP) in sensitizing cancer cells to GSK3368715. Deletion of the MTAP gene results in the accumulation of a metabolite called 2-methylthioadenosine, which acts as an endogenous inhibitor of PRMT5. The presence of this metabolite correlates with increased sensitivity to GSK3368715 in cell lines. Based on these findings, the report suggests exploring the status of MTAP as a potential biomarker strategy for selecting patients who may benefit from treatment with GSK3368715.

In summary, the report introduces GSK3368715 as a potent type I PRMT inhibitor with anti-tumor effects and suggests that combining its inhibition with PRMT5 inhibition could be beneficial in cancer treatment. It also highlights the potential use of MTAP status as a biomarker to identify patients who are likely to respond to GSK3368715.

Related Products

Cat.No. Product Name Information
S8858 GSK3368715 3HCl GSK3368715 3HCl is a potent inhibitor of type I protein arginine methyltransferases (PRMT) that inhibits PRMT1, 3, 4, 6 and 8 with Kiapp vaules ranging from 1.5 to 81 nM.

Related Targets

PRMT