Discovery of TNG462: A Highly Potent and SelectiveMTA-Cooperative PRMT5 Inhibitor to Target Cancers with <i>MTAP</i> Deletion

The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10–15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets <i>MTAP</i>-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in <i>MTAP</i>-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for <i>MTAP</i>-deleted cancers and is currently in Phase I/II clinical trials.