Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP -Deleted Cancers.
Christopher R SmithRuth ArandaThomas P BobinskiDavid M BriereAaron C BurnsJames G ChristensenJeffery ClarineLars D EngstromRobin J GunnAnthony IvetacRonald Jean-BaptisteJohn M KetchamMasakazu KobayashiJon KuehlerSvitlana KulykJ David LawsonKrystal MoyaPeter OlsonLisa RahbaekNicole C ThomasXiaolun WangLaura M WatersMatthew A MarxPublished in: Journal of medicinal chemistry (2022)
The PRMT5•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 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 protein modification in MTAP -deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2 H )-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 MRTX1719 .
Keyphrases
- induced apoptosis
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- combination therapy
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- mass spectrometry
- emergency department
- insulin resistance
- oxidative stress
- replacement therapy
- amino acid
- smoking cessation
- pi k akt