4 research outputs found

    MOESM2 of The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology

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    Additional file 2: Figure S1. Food consumption. (A) Average food consumption for mice fed G007-LK-enriched chow (100 mg G007-LK/kg chow) for 3 weeks. The grey curves represent average consumption per mouse for two animals housed in the same cage. The black curve illustrates the food consumption of one mouse housed alone

    MOESM4 of The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology

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    Additional file 4: Figure S3. BrdU incorporation. (A and B) Immunofluorescence labelling of duodenal tissue sections from control (A) and G007-LK enriched chow, 100 mg G007-LK/kg chow (B) treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice, stained with DAPI (blue) and antibodies against BrdU (red) and GFP (green). BrdU and GFP double positive cells are indicated with yellow arrows, BrdU positive cells with pink arrows and GFP positive (LGR5 expressing) cells with white arrows. (C and D) IHC of duodenal tissue sections, stained for BrdU incorporation after daily treatments with BrdU for 7 days. Cells with incorporated BrdU (indicated with black arrows) were identified at the tips of the duodenal villi in control (C) and G007-LK (100 mg G007-LK/kg chow) treated (D) mice. Images are 20× representations from high resolution scanned tissues slides (scale bar 300 μm)

    Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach

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    A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor <b>16</b> displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> 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

    Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach

    No full text
    A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor <b>16</b> displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> 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
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