Definition

An orally bioavailable inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration, PRMT5 inhibitor SYHX2001 selectively binds to PRMT5 and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including 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 overexpressed in several neoplasms and is essential for the viability of cancer and normal cells. Elevated levels are associated with decreased patient survival. Methylthioadenosine phosphorylase (MTAP) is deleted in certain cancer cells leading to an accumulation of methylthioadenosine (MTA). As MTA binds to and partially inhibits PRMT5, MTAP-null cancer cells are specifically sensitive to PRMT5 inhibitors. This may spare normal, healthy cells that are without MTAP-deletions and lower systemic toxicity.