Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of <i>MTAP</i>-Deleted Cancers

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of <i>MTAP</i>-deleted cancers. Here, we report the discovery of development candidate <b>MRTX1719</b>. <b>MRTX1719</b> is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in <i>MTAP</i>-deleted cells compared to <i>MTAP</i>-wild-type cells. Daily oral administration of <b>MRTX1719</b> to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in <i>MTAP</i>-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)­phthalazin-1­(2<i>H</i>)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate <b>MRTX1719</b>.