Protein arginine methyltransferase 5 (PRMT5), an epigenetic target with significant clinical potential, is closely associated with the occurrence and development of a range of tumours and has attracted considerable interest from the pharmaceutical industry and academic research communities. According to incomplete statistics, more than 10 PRMT5 inhibitors for cancer therapy have entered clinical trials in recent years. Among them, the second-generation PRMT5 inhibitors developed based on the synthetic lethal strategy demonstrate considerable clinical application value. This suggests that, following the precedent of poly ADP ribose polymerase (PARP), PRMT5 has the potential to become the next clinically applicable synthetic lethal target. However, due to the inherent dose-limiting toxicity of epigenetic target inhibitors, none of these PRMT5 inhibitors has been approved for marketing to date. In light of this, we have conducted a review of the design thoughts and the structure-activity relationship (SAR) of known methylthioadenosine (MTA)-cooperative PRMT5 inhibitors. Additionally, we have analysed the clinical safety of representative first- and second-generation PRMT5 inhibitors. This paper discusses the vulnerability of the aromatic amine moiety of the second-generation PRMT5 inhibitor based on its structure. It also considers the potential nitrosamine risk factors associated with the preparation process.