Abstract 462: TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss

Abstract 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, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. TNG456 is a next-generation, highly potent and selective MTA-cooperative PRMT5 inhibitor designed for patients with MTAP-null cancers including gliomas and other tumors which frequently metastasize to the brain, such as NSCLC. In vitro, TNG456 is 55X selective for MTAP-null cancer cell lines over isogenic MTAP WT cell lines (compared to 15X for TNG908) and has marked selectivity for MTAP-null cancer cell lines independent of lineage in a large, diverse cell line panel. TNG456 is brain-penetrant in preclinical species with a Kpuu range of 0.5-1.1 in non-human primates and dogs. Oral administration of TNG456 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-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases. Citation Format: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Wenhai Zhang, Alan Huang, Jannik N. Andersen, Kevin M. Cottrell. TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 462.