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TNG908 is an investigational PRMT5 inhibitor with a novel MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10-15% of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. TNG908 selectively binds the PRMT5-MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, which is postulated to create a large therapeutic index relative to PRMT5 inhibitors currently in clinical development. 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. In vitro mechanistic studies confirm that MTAPnull-selective PRMT5 inhibitors can selectively target MTAPnull cancer cells in either an admixture of MTAPnull and MTAPWT cells, or with intracellular MTA accumulation 2-5X relative to basal levels in MTAPWT cells. Oral administration of TNG908 drives dose-dependent, MTAPnull-selective antitumor activity in multiple xenograft models, including tumor regressions in models representing non-small cell lung cancer (adenocarcinoma and squamous), cholangiocarcinoma, urothelial carcinoma, and others. Preclinical studies suggest clinical combinations that leverage PRMT5 biology and/or concurrent oncogenic driver mutations, such as KRASG12C. In summary, TNG908 is a novel, potent 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. Citation Format: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik W. Wilker, Lina Gu, Charles B. Davis, Minjie Zhang, Doug Whittington, Deepali Gotur, Matthew J. Goldstein, Heather DiBenedetto, Marc S. Rudoltz, Alan Huang, John P. Maxwell. TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in MTAP-deleted xenograft models across multiple histologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3941. |
