Abstract
It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacokinetics
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Brain / metabolism
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Cell Line, Tumor
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Drug Discovery
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Humans
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Mice
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Neoplasms / drug therapy
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Protein-Arginine N-Methyltransferases* / antagonists & inhibitors
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Protein-Arginine N-Methyltransferases* / metabolism
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Protein-Arginine N-Methyltransferases
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PRMT5 protein, human
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Antineoplastic Agents
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Enzyme Inhibitors