The PRMT5/MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. However, clinically viable compounds that selectively bind and stabilize the complex have yet to be reported. Here, we report the discovery of a novel series of 4-(aminomethyl)phthalazin-1(2H)-one compounds identified via a fragment-based screen of 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 MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5/MTA complex, and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine (SDMA) protein modification in MTAP-deleted tumors that correlated with antitumor activity. In contrast, minimal inhibition of PRMT5-dependent SDMA and tumor growth inhibition was observed in MTAP-wild-type tumor xenografts. MRTX1719 possesses favorable drug-like characteristics, and was selected as a development candidate for the treatment of MTAP-deleted cancers.

Discovery of MRTX1719: A synthetic lethal inhibitor of the PRMT5/MTA complex for the treatment of MTAP-deleted cancers

ACS Spring 2022

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