75 (PB065) - Biochemical characterization of TNG908 as a novel, potent MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancers

Abstract

TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that leverages the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. PRMT5 is a type II arginine methyltransferase that regulates multiple essential cellular functions via symmetric dimethylation of arginine in target proteins. SAM is an essential co-factor for PRMT5, serving as the methyl donor when bound to a PRMT5-substrate protein complex. MTA is structurally similar to SAM but lacks the amino-carboxy terminus, therefore functions as an intrinsic inhibitor of PRMT5 when bound to a PRMT5-substrate protein complex.