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Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers

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posted on 2022-01-18, 21:09 authored by Christopher R. Smith, Ruth Aranda, Thomas P. Bobinski, David M. Briere, Aaron C. Burns, James G. Christensen, Jeffery Clarine, Lars D. Engstrom, Robin J. Gunn, Anthony Ivetac, Ronald Jean-Baptiste, John M. Ketcham, Masakazu Kobayashi, Jon Kuehler, Svitlana Kulyk, J. David Lawson, Krystal Moya, Peter Olson, Lisa Rahbaek, Nicole C. Thomas, Xiaolun Wang, Laura M. Waters, Matthew A. Marx
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.

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