Abstract 4970: TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors

Abstract MTAP deletions occur in 10-15% of all human cancers, which provides 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 is a clinical stage MTA-cooperative PRMT5 inhibitor 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 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. Oral administration of TNG462 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in cell line- and patient-derived xenograft models representative of clinically relevant histologies. Preclinical data suggest a low risk for drug-drug interactions, supporting clinical combination strategies. With enhanced potency and selectivity for MTAP-deleted cancer cells and improved pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in MTAP-deleted solid tumors than the MTA-cooperative PRMT5 currently being evaluated in clinical trials. Citation Format: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Matthew R. Tonini, Brian Haines, Alan Huang, Kevin M. Cottrell. TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts) ; 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83 (7Suppl): Abstract nr 4970.