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

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