Medicinal chemistry insights into PRMT5 inhibitors

[Display omitted] •In this paper, the structure and biological function of PRMT5 are introduced, and the published drugs are summarized according to their discovery methods.•In view of the current problems facing PRMT5 inhibitors, the paper summarizes the countermeasures and gives some new suggestions.•It includes comprehensive content and wide drug coverage. Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme that plays an important role in protein formation. PRMT5 is widely distributed in the nucleus and is involved in regulating a variety of biological processes, including gene transcription, signaling, and cell proliferation. PRMT5 regulates the function and stability of histones through methylation, affecting important cellular activities such as cell cycle regulation, DNA repair, and RNA processing. Studies have shown that PRMT5 is overexpressed in a variety of tumors and is closely related to the occurrence and development of tumors. In recent years, several PRMT5 inhibitors have entered clinical trials for the treatment of various cancers. In view of their importance, this paper reviews the first generation of PRMT5 inhibitors obtained by high-throughput screening, virtual screening, lead compound optimization and substitution modification, as well as novel PRMT5 inhibitors obtained by PROTAC technology and by synthetic lethal principle. Finally, by comparing the differences between the first generation and the second generation, the challenges and future development directions of PRMT5 inhibitors are discussed.