Peptoid inhibitors of Protein Arginine Methyltransferase 1 (PRMT1) for the treatment of Cancers

Bryan Knuckley

University of North Florida

Protein arginine methyltransferases (PRMTs) are a group of mammalian enzymes that are responsible for post-translational modification of proteins. These enzymes utilize S-adenosylmethionine (SAM) as a cofactor and are categorized into three types: Type I, II, and III. Type I PRMTs facilitate the transfer of two methyl groups from SAM to an arginine residue on the protein, yielding asymmetric dimethylarginine (ADMA). Similarly, Type II PRMTs add two methyl groups to the protein arginine, resulting in symmetric dimethylarginine (SDMA), while Type III PRMTs transfer a single methyl group, leading to monomethylarginine (MMA) formation. Our focus lies on the arginine methylation occurring on histone N-terminal tails, particularly Histone H4, which can modulate the expression of genes linked to various cancers (such as breast, colon, and prostate). Consequently, PRMTs serve as promising targets for cancer therapy, with peptides traditionally employed in developing lead compounds against this enzyme class. However, peptides' susceptibility to proteolysis limits their therapeutic efficacy and half-life. Peptoids, peptide mimics resistant to proteolysis, offer a solution. Thus, we have synthesized a peptoid-based compound selectively and irreversibly inhibiting PRMT1, a Type-I PRMT accounting for over 90% of mammalian arginine methylation. This inhibitor triggers apoptosis and autophagy in MDA-468 and HCT-116 cancer cell lines while exerting negligible effects on non-tumorigenic cell lines like HepaRG and normal Human Mammary Epithelial Cells (HMEC). These findings suggest its potential as a less cytostatic agent and position it as a lead peptoid compound for combating PRMT-induced cancers.