Protein arginine methyltransferase 3: Mechanism of action in diseases and modulator discovery.

Protein arginine methyltransferase 3 (PRMT3) is a key member of the PRMT family that catalyzes the arginine methylation of proteins, thereby modulating their structure, localization, or interactions and influencing essential physiological processes, such as cell growth and signal transduction. Its dysregulation is closely associated with tumorigenesis and neurological disorders. PRMT3 is critically involved in cellular processes, such as cell growth, invasion, and apoptosis, making it a promising target for drug discovery. In this review, we summarized the structure and biological functions of PRMT3, particularly the mechanism of action in human diseases. We also evaluated the co-crystal structure of PRMT3 inhibitors. Furthermore, we examined the recent advancements in the development of PRMT3 modulators, including isoform-selective and partially isoform-selective PRMT3 inhibitors as well as PRMT3-targeting PROTACs, from a rational design perspective. Finally, we discussed the existing challenges and future directions in PRMT3-targeted drug discovery.