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

TNG908 is a clinical stage PRMT5 inhibitor with an 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. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP -deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP -deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP -deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478). • TNG908 is a clinical-stage, brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP -deleted solid tumors • TNG908 is 15X selective for MTAP -deleted cancer cells relative to MTAP-proficient cells • TNG908 drives strong antitumor activity, including sustained tumor regressions, in MTAP -deleted xenograft models representing multiple tumor histologies including glioblastoma. • Novel combination partners for MTA-cooperative PRMT5 inhibitors identified by rational and functional genomics-based approaches include MAT2A and CDK4/6 inhibitors. • TNG908 is being tested clinically in a phase I/II trial in MTAP -deleted solid tumors including glioblastoma (NCT05275478).