TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancer

TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that leverages the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. TNG908 was discovered using structure-based design following an initial high-throughput screening campaign. TNG908 is 15X selective for MTAPnull cell lines over isogenic MTAPWT cell lines and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. Oral administration of TNG908 drives dose-dependent, MTAPnull-selective antitumor activity in xenograft models, including durable tumor regressions in models representing glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and others. TNG908 is brain-penetrant as exposure in the cerebrospinal fluid (CSF) approximates free, unbound plasma exposure in non-human primate studies. These data combined with strong preclinical activity in glioblastoma models strongly position TNG908 as a potential treatment of MTAP-deleted glioblastoma or solid tumor CNS metastases. A Phase 1/2 clinical trial (NCT05275478) is currently enrolling to assess safety, tolerability, and efficacy in patients with advanced or metastatic MTAP-deleted solid tumors, including non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, malignant peripheral nerve sheath tumor, or in a lineage-agnostic cohort. In summary, TNG908 is a clinical stage, potent, brain-penetrant PRMT5 inhibitor with excellent drug-like properties and strong preclinical activity in multiple xenograft models that has the potential for histology-agnostic clinical development in MTAP-deleted solid tumors. Conflict of interest: Ownership: All authors are full-time employees of Tango Therapeutics and have stock and/or stock options.