TNG908

Although several MTA-cooperative PRMT5 synthetic lethal inhibitors have been advanced into clinical trials, only one of them (TNG908) showed brain permeability in the preclinical evaluation but failed to achieve the anticipated therapeutic exposure levels in glioblastoma in clinical trials...More importantly, compound 21 achieved significant tumor growth inhibition in an orthotopic U87MG brain tumor model, supported by its enhanced distribution and penetration within brain tissue. These results indicate the potential clinical advantages of compound 21 for treating MTAP- deleted tumors and support its potential utility against intracranial malignancies.

P1/2, N=110, Terminated, Tango Therapeutics, Inc. | N=192 --> 110 | Active, not recruiting --> Terminated; Sponsor Decision - Business Decisions

This study investigates the effects of two classes of PRMT5 inhibitors, GSK3326595 and TNG908, on breast cancer cell lines with different BRCA1/2 statuses to evaluate their therapeutic potential and synergy with PARP inhibitors. These findings highlight the potential of combining PRMT5 inhibitors with PARP inhibitors in a wide range of cancers beyond BRCA1/2 and MTAP mutants. Further investigation is warranted to elucidate the underlying mechanisms of sensitization and the timing of cellular responses to PRMT5 inhibition.

P1/2, N=192, Active, not recruiting, Tango Therapeutics, Inc. | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Apr 2025 --> Dec 2025

Clinical stage MTA-cooperative PRMT5 inhibitors TNG908 and TNG462 are efficacious in MPNST models in vitro and in vivo; therefore MTA-cooperative PRMT5 inhibitors are promising therapeutic agents for patients with MTAP-deleted MPNST.

We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials.

P1/2, N=192, Active, not recruiting, Tango Therapeutics, Inc. | Recruiting --> Active, not recruiting

Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST.

In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).

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. As such, TNG908 may provide a novel treatment strategy for MTAP-deleted GBM patients. *MZ and AT contributed equally to the work.