Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy

Abstract

Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis. Additionally, we describe structure and catalytic activity of PRMT and discuss the mechanisms of action of novel small molecule inhibitors of specific members of the arginine methyltransferase family. Expert opinion: As the field of PRMT biology advances, it's becoming clear that this class of enzymes is highly relevant to maintaining normal physiologic processes as well and disease pathogenesis. We discuss the potential impact of PRMT inhibitors as a broad class of drugs, including the pleiotropic effects, off target effects the need for more detailed PRMT-centric interactomes, and finally, the potential for targeting this class of enzymes in clinical development of experimental therapeutics for cancer.

Keywords: Cancer; arginine-methylation; epigenetics; therapeutic target.

FIG. 1.

Domain architecture of nine human PRMTs. Abbreviated: SH3, SH3 domain; ZnF, zinc finger motif; PH, Pleckstrin homology domain; TPR, tetratricopeptide repeat.

FIG 2.

Crystal structures of PRMTs. Conserved catalytic core are shown in grey (Rossman fold in light grey while β-barrel in dark grey). Cofactor or its analogs are indicated in yellow, peptide is in green. TIM barrel domain of PRMT5 is colored in blue, the additional protein binding partner MEP50 is colored in orange. “Double E” loop is colored in pink and “THW” loop is in purple. PDB ID: PRMT1, 1OR8; PRMT3, 2FYT; PRMT4, 3B3M; PRMT5, 4GQB; PRMT6, 4HC4; PRMT7, 4M38; PRMT8, 4X41.

FIG. 3.

PRMT active sites display distinct spatial architectures. The active site of any PRMT can be roughly divided into two subregions: left (subregion A, colored in orange) or right (subregion B, colored in blue) side of the substrate arginine residue. Specifically, type I PRMTs contain a spatially restricted subregion A and an open subregion B, while type II PRMTs contain an open subregion A and a restricted subregion B. Type III contains two restrained subregions.

FIG. 4.

Examples of reported PRMT inhibitors.

FIG. 5.

Co-crystal structures of PRMTs and their inhibitors. A. Allosterically bound dimer of PRMT3-compound 8 (PDB: 4RYL); B. Active site of ternary complex CARM1-SAH-compound 9 (PDB: 2Y1W); C. Active site of quaternary complex PRMT5:MEP50-SAH-compound 14 (PDB: 4X61); D. Active site of ternary complex PRMT6-SAH-compound 16 (PDB: 4Y2H).