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.

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