ABSTRACT
MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.
Subject(s)
Enzyme Inhibitors , Neoplasms , Phthalazines , Humans , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Phthalazines/pharmacology , Protein-Arginine N-MethyltransferasesABSTRACT
The PRMT5â¢MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5â¢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 protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5â¢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.
