Discovery of\nPotent, Highly Selective, and Orally\nBioavailable MTA Cooperative PRMT5 Inhibitors with Robust <i>In Vivo</i> Antitumor Activity

Protein\narginine methyltransferase 5 (PRMT5), which catalyzes\nthe\nsymmetric dimethylation of arginine residues on target proteins, plays\na critical role in gene expression regulation, RNA processing, and\nsignal transduction. Aberrant PRMT5 activity has been implicated in\ncancers and other diseases, making it a potential therapeutic target.\nHere, we report the discovery of a methylthioadenosine (MTA) cooperative\nPRMT5 inhibitor. Compound <b>20</b> exhibited strong antiproliferation\nactivity in multiple MTAP-deleted cancer cell lines, excellent selectivity\nover MTAP wild-type cell lines, as well as satisfactory oral pharmacokinetic\nproperties over various preclinical species. Notably, compound <b>20</b> demonstrated a dose-dependent reduction of symmetric dimethylarginine\n(SDMA) expression in the LU99 cell line and robust <i>in vivo</i> antitumor activity in the LU99 subcutaneous model.