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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Deoxyadenosines / metabolism
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Female
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Gene Deletion
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Humans
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Mice
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Mice, Nude
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Neoplasms / drug therapy*
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Phthalazines / chemical synthesis
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Phthalazines / metabolism
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Phthalazines / therapeutic use*
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Protein Binding
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Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
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Protein-Arginine N-Methyltransferases / metabolism
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Purine-Nucleoside Phosphorylase / deficiency
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Purine-Nucleoside Phosphorylase / genetics
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Thionucleosides / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Deoxyadenosines
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Phthalazines
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Thionucleosides
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5'-methylthioadenosine
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Prmt5 protein, mouse
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Protein-Arginine N-Methyltransferases
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Purine-Nucleoside Phosphorylase
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5'-methylthioadenosine phosphorylase