Abstract
Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939)5, i.e., IC50 = 100 pM vs TNKS2 and IC50 = 6.5 μM vs PARP1 for 14. In cellular assays, 13 and 14 inhibited Wnt-signaling, enhanced insulin-stimulated glucose uptake, and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / chemical synthesis
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Aminoquinolines / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Glucose / metabolism*
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HEK293 Cells
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
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Protein Isoforms / antagonists & inhibitors
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Quinazolinones / chemical synthesis
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Quinazolinones / pharmacology*
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Tankyrases / antagonists & inhibitors*
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Wnt Signaling Pathway / drug effects*
Substances
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2-(3-oxo-3-(4-((quinolin-8-yl)aminocarbonyl)phenylamino)propyl)quinazolin-4-one
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8-methyl-2-(3-oxo-3-(4-((quinolin-8-yl)aminocarbonyl)phenylamino)propyl)quinazolin-4-one
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Aminoquinolines
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Antineoplastic Agents
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Heterocyclic Compounds, 3-Ring
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Poly(ADP-ribose) Polymerase Inhibitors
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Protein Isoforms
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Quinazolinones
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XAV939
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TNKS2 protein, human
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Tankyrases
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Glucose