AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers
One of the most consistently observed synthetic lethal interactions in functional genomic screens is the dependence of cancer cells with MTAP deletion on PRMT5. We report the discovery of AMG 193, a clinical-stage MTA-cooperative PRMT5 inhibitor, which selectively binds PRMT5 in the presence of MTA and exhibits potent biochemical and cellular activity in MTAP-deleted cancer cells across multiple lineages. In vitro, PRMT5 inhibition by AMG 193 induces DNA damage, cell cycle arrest, and dysregulated alternative mRNA splicing in MTAP-deleted cells. In both human cell line and patient-derived xenograft models, AMG 193 demonstrates significant antitumor activity while being well tolerated, with no adverse effects on normal hematopoietic cells. AMG 193 shows synergy with chemotherapy and the KRAS G12C inhibitor sotorasib in vitro, and combination therapy in vivo results in marked tumor growth inhibition. AMG 193 is currently exhibiting promising clinical activity, including confirmed partial responses AMG-193 in patients with MTAP-deleted solid tumors in an ongoing phase 1/2 trial.