From Scaffold to Selectivity-Medicinal insights of PRMT1 and PRMT4 inhibitors for Epigenetic Cancer Therapy

Abstract

PRMT1 and PRMT4 (CARM1) are the epigenetic regulators concerned with the methylation of arginine residues, acting on both the histone and non-histone proteins, regulating chromatin dynamics, gene expression and signaling pathways. Impaired control and imbalanced regulation of this induces various types of cancers. This review provides a comprehensive assessment of the structure-activity relationship (SAR) of various small-molecule inhibitors targeting PRMT1 and PRMT4. We identified a range of chemical frameworks like tetrazole, furan, thiazole, tetrahydroisoquinoline derivatives and many others. These derivatives act through various mechanisms to inhibit the overexpression of PRMT1 and PRMT4. Significant SAR insights underscore the essential role within individual structural motifs, including the contribution of electron-withdrawing and electron-donating groups, which depict the activity, selectivity and potency for inhibition, electrostatic interactions andπ-π stacking of structural units. Docking studies emphasize the key interaction of ligand molecules with the active site of the target. This review forms a solid foundation for the rational development of the next generation PRMT1 and PRMT4 inhibitors with better therapeutic potential by systematically correlating the chemical structure with biological activity across a number of classes through SAR and computational studies.