Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader

Protein arginine methyltransferase 5 (PRMT5) plays crucial roles in the regulation of various biological processes through the mono- and symmetric dimethylation of protein substrates. PRMT5 is overexpressed in various human cancers and its overexpression is associated with poor prognosis. We previously reported the first-in-class PRMT5 degrader, MS4322, which is also the only von Hippel-Lindau (VHL)-recruiting PRMT5 degrader to date. Here, we performed structure-activity relationship (SAR) studies exploring various linkers and ligands of VHL and PRMT5, which resulted in the best-in-class PRMT5 degrader, MS115 (compound <b>10</b>). Compound <b>10</b> potently and selectively degraded PRMT5 and its coactivator, MEP50, in concentration-, time-, and ubiquitin-proteasome system-dependent manners. It displayed much improved PRMT5/MEP50 degradation potency over MS4322, which translated to better antiproliferative effect in both breast and prostate cancer cells. Overall, we discovered a highly potent and selective PRMT5/MEP50 complex degrader, which is an invaluable chemical biology tool and a potential cancer therapeutic.