AM-9747

AM-9747 is a small molecule, MTA-cooperative inhibitor of Protein Arginine Methyltransferase 5 (PRMT5) developed by Amgen. It is designed to selectively target MTAP-null tumors, which represent approximately 15% of all human cancers. In cells with MTAP deletion, the metabolite methylthioadenosine (MTA) accumulates and binds to PRMT5, creating a unique binding pocket that MTA-cooperative inhibitors like AM-9747 exploit. By binding to the PRMT5-MTA complex, AM-9747 induces DNA damage, cell cycle arrest, and senescence. While Amgen's lead candidate AMG 193 is in clinical trials, AM-9747 serves as a representative analog for preclinical evaluation. It has demonstrated synergistic antitumor activity in combination with standard chemotherapies (such as paclitaxel and carboplatin) and targeted therapies (such as the KRAS G12C inhibitor sotorasib) in models of non-small cell lung cancer and pancreatic cancer.