Abstract
PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chemistry Techniques, Synthetic
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Drug Design*
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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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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacokinetics
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Isoquinolines / pharmacology
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / pathology
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Mice
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Models, Molecular
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Protein Conformation
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Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
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Protein-Arginine N-Methyltransferases / chemistry
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Stereoisomerism
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Tissue Distribution
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Xenograft Model Antitumor Assays
Substances
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Enzyme Inhibitors
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Isoquinolines
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Protein-Arginine N-Methyltransferases
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coactivator-associated arginine methyltransferase 1
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isoquinoline