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

Abstract

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 3 Pg. 1749-1766 (02 10 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35041419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Deoxyadenosines
• Phthalazines
• Thionucleosides
• 5'-methylthioadenosine
• Prmt5 protein, mouse
• Protein-Arginine N-Methyltransferases
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, therapeutic use)
• Cell Line, Tumor
• Deoxyadenosines (metabolism)
• Female
• Gene Deletion
• Humans
• Mice, Nude
• Neoplasms (drug therapy)
• Phthalazines (chemical synthesis, metabolism, therapeutic use)
• Protein Binding
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors, metabolism)
• Purine-Nucleoside Phosphorylase (deficiency, genetics)
• Thionucleosides (metabolism)
• Xenograft Model Antitumor Assays