PRMT5 Programs

PRMT5 is an essential gene required for cell survival, thus a potential cancer therapeutic target. However, non-synthetic lethal PRMT5 inhibitors kill normal cells – particularly those in the bone marrow – as effectively as cancer cells. The resulting hematologic toxicity means the dose of non-synthetic lethal PRMT5 inhibitors needed to kill cancer cells is difficult to deliver without causing unacceptable bone marrow suppression.

Normal cells

Normal cells
  • Most PRMT5 in normal cells is bound to SAM
  • PRMT5 requires SAM for activity
  • Non-synthetic lethal PRMT5 inhibitors suppress PRMT5 equally in normal and MTAP-del cells

MTAP-deleted
cancer cells

MTAP-deleted<br>cancer cells
  • Most PRMT5 in MTAP-deleted cells is bound to MTA
  • MTA-bound PRMT5 is inactive
  • Synthetic lethal PRMT5 inhibitors bind to the PRMT5-MTA complex

Opportunity

TNG908 and TNG462 are potent synthetic lethal inhibitors of PRMT5 (protein arginine methyl transferase 5) that work selectively in cancer cells with MTAP (methylthioadenosine phosphorylase) deletion, a common genetic alteration in a number of cancer types that does not occur in normal cells. Loss of MTAP leads to an accumulation of the inhibitory PRMT5 co-factor MTA (5’-deoxy-5’-methylthioadenosine). This increase in MTA markedly reduces PRMT5 activity in MTAP-deleted cancer cells but not in normal cells, and results in a vulnerability that makes MTAP-deleted cells more susceptible to PRMT5 inhibition than normal cells.

MTAP deletions occur in 10-15% of all human cancers, including many common cancers with limited treatment options such as non-small cell lung cancer (both squamous and non-squamous), mesothelioma, pancreatic cancer, cholangiocarcinoma, and glioblastoma (GBM) creating a potentially very significant therapeutic opportunity for patients.

TNG908

  • TNG908 is a synthetic lethal PRMT5 inhibitor that selectively kills cancer cells with MTAP deletions while sparing normal cells
  • In preclinical studies, TNG908 is 15 times more potent in MTAP-deleted cancer cells than in normal cells
  • TNG908 is blood-brain barrier penetrant in preclinical studies, affording an opportunity to address an unmet medical need in GBM where ~40% of patients harbor MTAP loss

TNG462

  • TNG462, our next-generation PRMT5 inhibitor, has the same mechanism of action as TNG908 with enhanced potency and selectivity in MTAP-deleted xenograft models
  • Additional potency may provide even stronger target inhibition and thus clinical efficacy, and additional selectivity for MTAP-deleted cells may provide an even wider therapeutic index
  • In preclinical studies, TNG462 is 45 times more potent in MTAP-deleted cancer cells than in normal cells

180 cancer cell lines from multiple lineages

180 cancer cell lines from multiple lineages

7-day viability assay
Same cell lines represented in all panels

Learn more about our Target 3 program.Learn more about our Target 3 program.