PRMT5 inhibitor TNG456

An orally bioavailable, blood-brain-barrier (BBB) penetrant and methylthioadenosine (MTA)-selective inhibitor of the protein arginine methyltransferase 5 (PRMT5), with potential antineoplastic activity. Upon oral administration, PRMT5 inhibitor TNG456 targets, binds to and inhibits PRMT5 that is bound to MTA, thereby specifically inhibiting the function of PRMT5 solely within methylthioadenosine phosphorylase (MTAP)-deleted cancer cells and not in normal, healthy cells. By inhibiting the methyltransferase activity of PRMT5, levels of both monomethylated and dimethylated arginine residues in certain histones and non-histone proteins are decreased. This modulates the expression of genes involved in several cellular processes and may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation. This may lead to decreased growth of rapidly proliferating cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is essential for the viability of cancer and normal cells. It is overexpressed in several neoplasms and elevated levels are associated with decreased patient survival. MTAP is deleted in certain cancer cells leading to an accumulation of the metabolite MTA. As MTA binds to and inhibits the activity of PRMT5, MTAP-deficient cancer cells are specifically sensitive to PRMT5 inhibitors.