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

• Published in: Journal of medicinal chemistry Vol. 65; no. 3; pp. 1749 - 1766
• Main Authors: Smith, Christopher R, 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, Moya, Krystal, Olson, Peter, Rahbaek, Lisa, Thomas, Nicole C, Wang, Xiaolun, Waters, Laura M, Marx, Matthew A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-02-2022
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Deoxyadenosines - metabolism; Female; Gene Deletion; Humans; Mice; Mice, Nude; Neoplasms - drug therapy; Phthalazines - chemical synthesis; Phthalazines - metabolism; Phthalazines - therapeutic use; Protein Binding; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - metabolism; Purine-Nucleoside Phosphorylase - deficiency; Purine-Nucleoside Phosphorylase - genetics; Thionucleosides - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01900

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.