TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of peripheral MTAP-deleted solid tumors

MTAP deletions occur in 10–15% of all human cancers, providing one of the largest precision oncology patient populations. MTA-cooperative PRMT5 inhibitors leverage the well-characterized synthetic lethal relationship between PRMT5 inhibition and MTAP-deletion. TNG908, AMG 193, and MRTX1719 are all clinical stage MTA-cooperative PRMT5 inhibitors for the treatment of MTAP-deleted solid tumors. TNG462 is an investigational stage MTA-cooperative PRMT5 inhibitor with significantly enhanced potency, selectivity and extended target coverage designed to be a best-in-class treatment for patients with peripheral MTAP-deleted cancer. In vitro, TNG462 is 45X selective for MTAP-deleted cancer cell lines over isogenic MTAP WT cell lines and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. TNG462 demonstrates durable PD modulation in vitro and in vivo consistent with high affinity binding to PRMT5. Oral administration of TNG462 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-deleted cancer cells, and optimized pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in peripheral MTAP-deleted solid tumors. Conflict of interest: Ownership: All of the authors are full-time Tango employees and have stocks and/or stock options.