MRTX1719, an MTA-cooperative PRMT5 Inhibitor, Induces Cell Cycle Arrest and Synergizes With Oxaliplatin and Gemcitabine for Enhanced Anticancer Effects.

Abstract

Background/aim: MRTX1719 is a novel protein arginine methyltransferase 5 (PRMT5) inhibitor that targets the PRMT5-5'-Methylthioadenosine (MTA) complex called MTA-cooperative PRMT5 inhibitor. MRTX1719 acts specifically on methylthioadenosine phosphorylase (MTAP)-deficient cancer cells; however, its mechanism of action remains unclear. This study aimed to clarify the effects of MRTX1719 on the cell cycle and its synergistic effects with other anticancer drugs.

Materials and methods: A cell cycle assay was conducted using fluorescence-activated cell sorting to examine the correlation between PRMT5 activity and cells in the G₀/G₁ phase. The synergistic effects of MRTX1719 and anticancer drugs were evaluated using the Combination Index (CI) and Bliss synergy score (BSS). The synergistic effect was also evaluated by knocking down the endogenous expression of MTAP in HCT116 cells with high MTAP expression.

Results: The cell cycle assay showed that the population of cells with reduced PRMT5 activity increased, and the administration of MRTX1719, an MTAP inhibitor, increased the population of cells in the G₀/G₁ phase. In the synergistic effect assay, oxaliplatin and gemcitabine demonstrated a CI <1 and a BSS >0, indicating a synergistic effect when administered alongside MRTX1719. MTAP knockdown also resulted in <1 in CI and >0 in BSS after the administration of oxaliplatin or gemcitabine with MRTX1719.

Conclusion: MRTX1719 reduces PRMT5 activity, leading to cell cycle arrest by increasing the proportion of cells in the G₀/G₁ phase. Moreover, MRTX1719 exhibits synergistic anticancer effects with oxaliplatin and gemcitabine in MTAP-deficient cancer cells.