TNG908

TNG908 is an orally available, brain-penetrant small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) that acts through an MTA-cooperative binding mechanism. It is designed to exploit the synthetic lethal interaction between PRMT5 inhibition and MTAP (methylthioadenosine phosphorylase) deletion, a genetic alteration present in approximately 10–15% of human cancers across multiple histologies. In MTAP-deleted cancer cells, accumulation of MTA (methylthioadenosine) enhances the selectivity of TNG908 for tumor cells by promoting its binding to the PRMT5·MTA complex, resulting in potent and selective inhibition of PRMT5 activity while sparing normal cells. This mechanism provides a large therapeutic index compared to earlier PRMT5 inhibitors that lack tumor selectivity. Preclinical studies have demonstrated strong antitumor activity in various MTAP-deleted xenograft models and confirmed brain penetrance. Clinically, TNG908 has been evaluated in Phase I/II trials for patients with advanced or metastatic solid tumors harboring MTAP deletions, including glioblastoma. Clinical development for glioblastoma was halted due to insufficient efficacy. TNG908 showed efficacy signals in non-CNS tumors such as non-small cell lung cancer and pancreatic cancer. The drug received FDA Orphan Drug Designation for malignant peripheral nerve sheath tumor (MPNST) and malignant glioma.

Other names

Ralometostat