AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been the dependency on protein arginine methyltransferase 5 (PRMT5) in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro and combination treatment in vivo substantially inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study. Significance: AMG 193 preferentially inhibits the growth of MTAP-deleted tumor cells by inhibiting PRMT5 when in complex with MTA, thus sparing MTAP wild-type normal cells. AMG 193 shows promise as a targeted therapy in a clinically defined patient population.