Protein arginine methyltransferase 5-Methylthioadenosine complex (PRMT5-MTA) (PRMT5-MTA)

The Protein arginine methyltransferase 5-Methylthioadenosine (PRMT5-MTA) complex is a specific molecular state of the PRMT5 enzyme that serves as a precision oncology target [1, 3]. PRMT5 is a type II methyltransferase that, in complex with MEP50, catalyzes the symmetric dimethylation of arginine residues on various proteins involved in RNA splicing, gene expression, and the cell cycle [4, 11]. In approximately 10-15% of human cancers, the methylthioadenosine phosphorylase (MTAP) gene is homozygously deleted, leading to the accumulation of the metabolite methylthioadenosine (MTA) [1, 5]. This accumulated MTA binds to PRMT5, forming the PRMT5-MTA complex and partially inhibiting its activity, which creates a unique synthetic lethal vulnerability in these tumor cells [3, 4]. Second-generation PRMT5 inhibitors are designed to be MTA-cooperative, meaning they selectively bind to and stabilize the PRMT5-MTA complex rather than the PRMT5-SAM complex found in normal cells [4, 6]. This selectivity allows for the potent inhibition of PRMT5 activity specifically in MTAP-deleted cancer cells while sparing healthy tissues, thereby significantly reducing the hematological toxicities associated with first-generation, non-selective PRMT5 inhibitors [8, 12]. Clinical development of these inhibitors, such as MRTX1719 and AMG 193, focuses on treating a wide range of MTAP-deleted solid tumors, including lung, pancreatic, and brain cancers [2, 8, 9].

Other names

PRMT5/MTA complexMTA-bound PRMT5PRMT5-MEP50-MTA complexPRMT5-MTA axis

MTA-cooperative inhibition, synthetic lethality, and substrate-competitive inhibition