Abstract 3452: TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models

Glioblastoma multiforme (GBM) is one of the most aggressive primary malignant brain tumors in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) on standard of care therapies, which include surgery, radiotherapy, and the alkylating agent temozolomide. Therefore, developing new treatments for GBM is an urgent unmet medical need. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that inhibits PRMT5 activity selectively in MTAP-null cells leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors are homozygous null for MTAP [1, 2]. In preclinical in vitro studies, the antiproliferation activity of TNG908 was 15 times more potent in MTAP-null cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is not a substrate for P-glycoprotein nor Breast Cancer Resistant Protein efflux transporters, attributes which are favorable for crossing the blood-brain barrier. TNG908 demonstrated in vivo brain penetration in multiple preclinical studies, including non-human primates and mice, suggesting that TNG908 may fulfill the significant unmet need in the treatment of GBM. Pharmacodynamic activity of TNG908 to inhibit PRMT5 was demonstrated by decreased SDMA-modified protein levels in a dose-dependent manner in a GBM xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite reduced Kpuu in rodents compared to primates, oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant small molecule PRMT5 inhibitor that is selective for MTAP-null tumor cells with good drug-like properties and strong antitumor activity in preclinical models of GBM. As such, TNG908 may provide a novel treatment strategy for MTAP-deleted GBM patients. *MZ and AT contributed equally to the work. Reference: 1.Cerami et al., Cell, 2013. 2.Gao et al., Sci Signal, 2013 Citation Format: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Erik Wilker, Heather DiBenedetto, Ron Weitzman, Alan Huang, Charles B. Davis, John P. Maxwell, Kimberly J. Briggs. TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models [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(7_Suppl):Abstract nr 3452.