Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with <i>MTAP</i>-Deleted Cancers

Abstract

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the <i>MTAP</i> gene if the inhibitors can leverage the consequence of <i>MTAP</i> deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of <i>MTAP</i>-deleted (MTAP-null) cells compared to <i>MTAP</i>intact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with <i>MTAP</i> loss.