Discovery ofAMG 193, an MTA-Cooperative PRMT5 Inhibitorfor the Treatment of <i>MTAP</i>-Deleted Cancers

<i>MTAP</i> deletion occurs in 10–15% of all human cancers due to its proximity to the tumor suppressor gene <i>CDKN2A</i>. The loss of MTAP leads to accumulation of methylthioadenosine (MTA), which shares structural similarity to <i>S</i>-adenosyl methionine (SAM), the methyl donor for the cell-essential protein arginine methyltransferase 5 (PRMT5). By competing with SAM, MTA partially inhibits PRMT5, making <i>MTAP</i>-deleted tumors susceptible to further PRMT5 inhibition. Herein, we report the discovery of MTA-cooperative PRMT5 inhibitor <b>AMG 193</b>, a molecule that inhibited the proliferation of HCT116 <i>MTAP</i>-deleted cells with ∼40x selectivity over HCT116 <i>MTAP</i>-WT cells. <b>AMG 193</b> was orally efficacious in mouse xenografts of endogenous <i>MTAP</i>-null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD) and U87MG (88% TGI @ 100 mg/kg QD). Preclinical data indicate that <b>AMG 193</b> is brain-penetrant. <b>AMG 193</b> is currently in Phase I/II clinical trials for the treatment of advanced <i>MTAP</i>-deleted solid tumors.