Abstract
Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases / antagonists & inhibitors*
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cytochrome P-450 CYP1A2 Inhibitors / administration & dosage
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Cytochrome P-450 CYP1A2 Inhibitors / chemical synthesis
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Cytochrome P-450 CYP1A2 Inhibitors / pharmacokinetics
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Cytochrome P-450 CYP1A2 Inhibitors / pharmacology
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Cytochrome P-450 CYP2D6 Inhibitors / administration & dosage
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Cytochrome P-450 CYP2D6 Inhibitors / chemical synthesis
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Cytochrome P-450 CYP2D6 Inhibitors / pharmacokinetics
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Cytochrome P-450 CYP2D6 Inhibitors / pharmacology
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Cytochrome P-450 CYP3A Inhibitors / administration & dosage
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Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
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Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
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Cytochrome P-450 CYP3A Inhibitors / pharmacology
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Female
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HEK293 Cells
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High-Throughput Screening Assays
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Humans
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Maleimides / administration & dosage
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Maleimides / chemical synthesis
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Maleimides / pharmacokinetics
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Maleimides / pharmacology*
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Membrane Proteins / antagonists & inhibitors*
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Mice, Inbred BALB C
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Mice, Nude
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Microsomes, Liver / metabolism
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Pyridazines / administration & dosage
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Pyridazines / chemical synthesis
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Pyridazines / pharmacokinetics
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Pyridazines / pharmacology*
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Rats
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Structure-Activity Relationship
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Wnt Signaling Pathway
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Xenograft Model Antitumor Assays
Substances
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2-(6-cyclopropyl-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H-pyrrolo(3,4-b)pyridin-1-yl)-N-(6-(pyridin-3-yl)pyridazin-3-yl)acetamide
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Antineoplastic Agents
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Cytochrome P-450 CYP1A2 Inhibitors
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Cytochrome P-450 CYP2D6 Inhibitors
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Cytochrome P-450 CYP3A Inhibitors
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Maleimides
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Membrane Proteins
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Pyridazines
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Acyltransferases
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PORCN protein, human
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Porcn protein, mouse