Discovery of MTA-cooperative PRMT5 Inhibitors

PRMT5 (protein arginine methyltransferase 5) plays an important role in the regulation of diverse cellular processes via symmetric dimethylation of target proteins involved in splicing regulation, cell cycle progression, apoptosis, the DNA-damage response, and other functions. Due to its involvement in these critical functions, PRMT5 is considered an essential gene. Approximately 10–15% of all human cancers have loss of methylthioadenosine phosphorylase (MTAP) resulting in the accumulation of methylthioadenosine (MTA). Small molecules that leverage this accumulation of cellular MTA and inhibit PRMT5 in an MTA-cooperative manner can exploit the synthetic lethal relationship between PRMT5 and MTAP deletion and are now being studied in human clinical trials. This chapter reviews the basics of PRMT5 biology and the three different hit finding approaches that resulted in the current clinical MTA-cooperative PRMT5 inhibitors.