138887-02-2Relevant articles and documents
Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5?MTA Complex for the Treatment of MTAP-Deleted Cancers
Aranda, Ruth,Bobinski, Thomas P.,Briere, David M.,Burns, Aaron C.,Christensen, James G.,Clarine, Jeffery,Engstrom, Lars D.,Gunn, Robin J.,Ivetac, Anthony,Jean-Baptiste, Ronald,Ketcham, John M.,Kobayashi, Masakazu,Kuehler, Jon,Kulyk, Svitlana,Lawson, J. David,Marx, Matthew A.,Moya, Krystal,Olson, Peter,Rahbaek, Lisa,Smith, Christopher R.,Thomas, Nicole C.,Wang, Xiaolun,Waters, Laura M.
supporting information, p. 1749 - 1766 (2022/02/05)
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(2H)-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.
