Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion

High Resolution Image Download MS PowerPoint Slide 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 MTAP -deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP -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 MTAP -deleted cancers and is currently in Phase I/II clinical trials.