Targeting PRMTs with Small-Molecule Inhibitors: A Comprehensive Review

Protein arginine methyltransferases (PRMTs) constitute a family of S-adenosyl-l-methionine (SAM)-dependent enzymes responsible for the methylation of arginine residues on histone and non-histone proteins. Through this post-translational modification, PRMTs regulate diverse cellular processes, including chromatin dynamics, transcriptional control, RNA metabolism, and the DNA damage response. Increasing evidence links aberrant PRMT activity to tumourigenesis and other pathological conditions, positioning these enzymes as attractive targets for pharmacological intervention. In recent years, extensive medicinal chemistry campaigns have led to the identification of a wide range of small-molecule PRMT modulators. Distinct inhibitor classes have been developed to exploit different binding regions within the catalytic machinery, including SAM-competitive ligands, substrate-pocket binders, and bisubstrate analogues capable of simultaneously engaging both sites. For some isoforms, particularly PRMT5, these strategies have yielded compounds with strong biochemical potency, robust cellular activity, and encouraging pharmacological profiles. In parallel, inhibitors targeting PRMT1, PRMT4 (CARM1), PRMT6, and PRMT7 have emerged as valuable chemical probes to investigate the biological roles of these enzymes. More recently, innovative approaches—such as methylthioadenosine (MTA)-cooperative inhibitors designed to exploit methylthioadenosine phosphorylase (MTAP)-deleted tumours and targeted protein degradation (TPD) strategies—have further expanded the therapeutic landscape. This review summarizes the current state of small-molecule PRMT modulation, highlighting representative chemotypes, binding modes, and structure–activity relationships (SARs) reported across individual PRMT isoforms. Particular attention is given to compounds that have advanced into preclinical or clinical evaluation, alongside emerging strategies aimed at improving selectivity and therapeutic applicability. Collectively, these advances illustrate the rapid evolution of PRMT-directed medicinal chemistry and its growing relevance to the development of targeted epigenetic therapies.