G007-LK

tankyrase 1/2 inhibitor CAS# 1380672-07-0

G007-LK

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Chemical structure

G007-LK

3D structure

Chemical Properties of G007-LK

Cas No. 1380672-07-0 SDF Download SDF
PubChem ID 67960134 Appearance Powder
Formula C25H16ClN7O3S M.Wt 529.96
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 30 mg/mL (56.61 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-[5-[(E)-2-[4-(2-chlorophenyl)-5-(5-methylsulfonylpyridin-2-yl)-1,2,4-triazol-3-yl]ethenyl]-1,3,4-oxadiazol-2-yl]benzonitrile
SMILES CS(=O)(=O)C1=CN=C(C=C1)C2=NN=C(N2C3=CC=CC=C3Cl)C=CC4=NN=C(O4)C5=CC=C(C=C5)C#N
Standard InChIKey HIWVLHPKZNBSBE-OUKQBFOZSA-N
Standard InChI InChI=1S/C25H16ClN7O3S/c1-37(34,35)18-10-11-20(28-15-18)24-31-29-22(33(24)21-5-3-2-4-19(21)26)12-13-23-30-32-25(36-23)17-8-6-16(14-27)7-9-17/h2-13,15H,1H3/b13-12+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of G007-LK

DescriptionG007-LK is a potent and selective inhibitor of TNKS1 and TNKS2, with IC50s of 46 nM and 25 nM, respectively.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)[1]. 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[3].In Vivo:G007-LK displays great pharmacokinetic profile in ICR mice[1]. 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[2].

References:
[1]. Voronkov A, et al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem. 2013 Apr 11;56(7):3012-23. [2]. Norum JH, et al. The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology. Biol Res. 2018 Jan 9;51(1):3. [3]. Xin Chen, et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One. 2017 Sep 6;12(9):e0184068.

Protocol

Cell Assay [3]
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). Cell proliferation is analyzed using the BrdU Cell Proliferation Assay Kit, while apoptosis is assessed with the Cell Death Detection Elisa Plus Kit[3].

Animal Administration [2]
Drug treatment experiments are performed with wild type (wt), single or double transgenic Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice, unless indicated otherwise. G007-LK is administered orally either by gavage (10 or 50 mg/kg body mass once daily, vehicle: 15% dimethylsulfoxide [DMSO], 17.5% Cremophor EL, 8.75% Miglyol 810 N, 8.75% ethanol in phosphate buffered saline [PBS]) or in G007-LK enriched chow (100 or 1000 mg G007-LK/kg chow ad libitum, corresponding to a daily G007-LK dose of approximately 20 or 200 mg/kg body mass, respectively, for a mouse with a body mass of 25 g and consumption of approximately 5 g enriched diet/day). G007-LK treatments are initiated at the age of 5 weeks and 5 days for oral gavage treatment or 6 weeks for enriched chow administration and continued for 9 or 21 days, respectively[2].

References:
[1]. Voronkov A, et al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem. 2013 Apr 11;56(7):3012-23. [2]. Norum JH, et al. The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology. Biol Res. 2018 Jan 9;51(1):3. [3]. Xin Chen, et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One. 2017 Sep 6;12(9):e0184068.

G007-LK Dilution Calculator

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G007-LK Molarity Calculator

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Preparing Stock Solutions of G007-LK

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8869 mL 9.4347 mL 18.8693 mL 37.7387 mL 47.1734 mL
5 mM 0.3774 mL 1.8869 mL 3.7739 mL 7.5477 mL 9.4347 mL
10 mM 0.1887 mL 0.9435 mL 1.8869 mL 3.7739 mL 4.7173 mL
50 mM 0.0377 mL 0.1887 mL 0.3774 mL 0.7548 mL 0.9435 mL
100 mM 0.0189 mL 0.0943 mL 0.1887 mL 0.3774 mL 0.4717 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on G007-LK

G007-LK is a potent and specific inhibitor of tankyrase 1/2 with IC50 values of 46 and 25 nM [1].

The telomeric repeat factor 1 (TRF1)-interacting ankyrin-related ADP-ribose polymerase 1 (tankyrase 1,TNKS1) and tankyrase 2 (TNKS2) belong to the subgroup of poly(ADP-ribosyl)ating polymerases and regulate the assembly and disassembly of large polymerized structures [1].

G007-LK is a potent and specific tankyrase 1/2 inhibitor. G007-LK reduced auto-poly-(ADP ribosy)lation of TNKS1 and TNKS2 with IC50 values of 46 nM and 25 nM, respectively. In Wnt3a-induced HEK 293 cells, G007-LK inhibited ST-Luc with IC50 value of 0.05 μM [1]. In SW480 colorectal cancer cell line transfected with GFP-TNKS1, G007-LK induces highly dynamic and mobile degradasomes containing phosphorylated beta-catenin, beta-TrCP and ubiquitin [2]. In the APC-mutant cell lines, G007-LK reduces cytosolic and nuclear β-catenin protein levels [3].

In mice bearing COLO-320DM cell xenografts, G007-LK (20 mg/kg twice daily or 40 mg/kg daily) concentration-dependently inhibited tumor growth by 61% and 48%, respectively. Also, G007-LK reduced the levels of TNKS1/2 and β-catenin, and stabilized AXIN1/2 [3].

References:
[1].  Voronkov A, Holsworth DD, Waaler J, et al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem, 2013, 56(7): 3012-3023.
[2].  Thorvaldsen TE, Pedersen NM, Wenzel EM, et al. Structure, Dynamics and Functionality of Tankyrase Inhibitor-induced Degradasomes. Mol Cancer Res, 2015, pii: molcanres.0125.2015.
[3].  Lau T, Chan E, Callow M, et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res, 2013, 73(10): 3132-3144.

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References on G007-LK

Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor.[Pubmed:23473363]

J Med Chem. 2013 Apr 11;56(7):3012-23.

Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triaz ol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 A resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound's high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.

Description

G007-LK is a potent and selective inhibitor of TNKS1 and TNKS2, with IC50s of 46 nM and 25 nM, respectively.

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