TNG908

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.

P1/2, N=170, Recruiting, Tango Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1/2, N=170, Not yet recruiting, Tango Therapeutics, Inc.

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.

These data suggest that treatment of KRASG12C-mutant lung adenocarcinoma with TNG908 and a KRASG12C inhibitor may be of clinical benefit in lung cancers with concurrent MTAP deletion and KRASG12C mutation.