PRMT5: A Promising Synthetical Lethal Target for MTAP-Deleted Cancers

PRMT5 is a promising target for cancer therapy. However, the first-generation PRMT5 inhibitors failed in the clinical trials due to the dose-limiting hematological toxicities, which could be attributed to the indiscriminate blockade of PRMT5 and the critical function of PRMT5 as an essential gene in regulating hematopoiesis. The second-generation MTA-cooperative PRMT5 synthetic lethal inhibitors could selectively inhibit PRMT5 activity in MTAP-del cancer cells while preserving its potency in MTAP-WT cells, presenting a promising precision oncology medicine. In this perspective, we analyzed the different binding modes between PRMT5·MTA and PRMT5·SAM complexes and highlighted the discovery of the second-generation MTA-cooperative PRMT5 inhibitors with the guidance of their cocrystal structures bound to the PRMT5·MTA complex. We also discussed the challenges and opportunities of these synthetic lethal inhibitors to shed light on future drug development.