In vitro: G007-LK is a potent inhibitor of TNKS1 and TNKS2, with IC50s of 46 nM and 25 nM, respectively, and a cellular IC50 of 50 nM. G007-LK shows no inhibition of PARP1 at doses up to 20 μM, and has a high CYP3A4 inhibition IC50 value (>25 μM). G007-LK (0-20 μM) dose-dependently inhibits hepatocellular carcinoma (HCC) cell growth. G007-LK also downregulates the levels of YAP by upregulating AMOTL1 and AMOTL2 in HCC cell lines. In addition, G007-LK (0-20 μM) synergizes with MEK and AKT inhibitors to suppress HCC cell proliferation.
In vivo: G007-LK displays great pharmacokinetic profile in ICR mice. G007-LK (100 mg/kg chow, p.o.) significantly reduces lineage tracing from LGR5+ intestinal stem cells in mice. G007-LK (100 mg/kg chow, p.o.) specifically targets LGR5+ WNT-dependent intestinal stem cells in Lgr5-EGFP-CreERT2;R26R-tdTomato mice. G007-LK (10, 50 mg/kg, p.o.) also suppressses canonical WNT signalling. Furthermore, G007-LK (100, 1000 mg/kg chow, p.o) shows no effect on the alteration of duodenal morphology.
| Cell Experiment | |
|---|---|
| Cell lines | SNU-449 and HLE cells |
| Preparation method | For cell proliferation or apoptosis assays, SNU-449 and HLE cells are grown in a 5% CO2 atmosphere, at 37°C, in RPMI Medium supplemented with 10% fetal bovine serum (FBS) and penicillin/streptomycin. HCC cells are treated with 0.1% DMSO, or 2.5 μM, 5 μM, 10 μM, 20μM XAV-939 or G007-LK, either alone or in combination with the MEK inhibitor U0126 (25 μM) or the AKT inhibitor MK-2206 (5 μM). |
| Concentrations | 2.5 μM, 5 μM, 10 μM, 20μM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | R26R-Confetti mice |
| Formulation | 15% DMSO, 17.5% Cremophor EL, 8.75% Miglyol 810 N, 8.75% ethanol in PBS |
| Dosages | 10 or 50 mg/kg |
| Administration | orally |
| Molecular Weight | 529.96 |
| Formula | C25H16ClN7O3S |
| CAS Number | 1380672-07-0 |
| Solubility (25°C) | 30 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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