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.
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.