Abstract
A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Chemistry Techniques, Synthetic
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Crystallography, X-Ray
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Dogs
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Drug Design
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / administration & dosage
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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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Inhibitory Concentration 50
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Male
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Mice, Inbred BALB C
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Poly(ADP-ribose) Polymerase Inhibitors / chemistry
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Rats, Sprague-Dawley
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Tankyrases / antagonists & inhibitors*
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Tankyrases / chemistry
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Tankyrases / metabolism
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Xenograft Model Antitumor Assays
Substances
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Enzyme Inhibitors
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Poly(ADP-ribose) Polymerase Inhibitors
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TNKS2 protein, human
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Tankyrases