G007-LK 1380672-07-0_PARP_DNA Damage_Signaling Pathways_Products

G007-LK is a novel, potent and specific tankyrase (TNKS) 1/2 inhibitor with potential anticancer activity. Its respective IC50s for inhibiting TNKS 1/2 are 46 nM and 25 nM. ADP ribosylation of TNKS1 and TNKS2 was decreased by G007-LK. In vivo antitumor efficacy is also high, and it exhibits strong antiproliferative activity against a variety of cancer cells. G007-LK has an IC50 value of 0.05 μM and inhibits ST-Luc in HEK 293 cells that have been induced with Wnt3a. Using the GFP-TNKS1-transfected SW480 colorectal cancer cell line, G007-LK generates phosphorylated beta-catenin, beta-TrCP, and ubiquitin-containing highly dynamic and mobile degradasomes. G007-LK lowers nuclear and cytosolic β-catenin protein levels in the APC-mutant cell lines.

Physicochemical Properties

Molecular Formula

C25H16CLN7O3S

Molecular Weight

529.96

Exact Mass

529.072

Elemental Analysis

C, 56.66; H, 3.04; Cl, 6.69; N, 18.50; O, 9.06; S, 6.05

CAS #

1380672-07-0

Related CAS #

1380672-07-0

PubChem CID

67960134

Appearance

Off-white to yellow solid powder

LogP

5.559

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

961

Defined Atom Stereocenter Count

SMILES

ClC1=C([H])C([H])=C([H])C([H])=C1N1C(/C(/[H])=C(\[H])/C2=NN=C(C3C([H])=C([H])C(C#N)=C([H])C=3[H])O2)=NN=C1C1C([H])=C([H])C(=C([H])N=1)S(C([H])([H])[H])(=O)=O

InChi Key

HIWVLHPKZNBSBE-OUKQBFOZSA-N

InChi Code

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+

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

Synonyms

G00 7LK; G007-LK; G007LK

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

TNKS2 ( IC50 = 25 nM ); TNKS1 ( IC50 = 46 nM )

ln Vitro

G007-LK exhibits strong inhibitory effects on both TNKS1 and TNKS2, as evidenced by its IC50 values of 46 nM and 25 nM, respectively, and its cellular IC50 of 50 nM. G007-LK has a high IC50 value (>25 μM) for CYP3A4 inhibition and exhibits no inhibition of PARP1 at doses up to 20 μM[1]. Hepatocellular carcinoma (HCC) cell growth is dose-dependently inhibited by G007-LK (0-20 μM). Additionally, in HCC cell lines, G007-LK decreases YAP levels by upregulating AMOTL1 and AMOTL2. Furthermore, G007-LK (0-20 μM) suppresses the proliferation of HCC cells by working in concert with MEK and AKT inhibitors[3].

ln Vivo

G007-LK exhibits an excellent pharmacokinetic profile in ICR mice.[1] In mice with LGR5⁺ intestinal stem cells, G007-LK (100 mg/kg chow, p.o.) dramatically decreases lineage tracing. To specifically target LGR5+ WNT-dependent intestinal stem cells in Lgr5-EGFP-CreERT2;R26R-tdTomato mice, G007-LK (100 mg/kg chow, p.o.) is administered. The suppressor of canonical WNT signaling is G007-LK (10, 50 mg/kg, p.o.). Moreover, there is no discernible change in the duodenal morphology when G007-LK (100, 1000 mg/kg chow, p.o.) is administered.

Enzyme Assay

TNKS1 and TNKS2 in vitro biochemical assays: G007-LK inhibitory activity is examined twice against TNKS1, TNSK2 Chemiluminescent Assay Kits at different dosages (duplicates), and the luminescence is gauged using a GloMax Luminometer.

Cell Assay

In order to conduct assays on cell proliferation or apoptosis, SNU-449 and HLE cells are cultured in RPMI Medium supplemented with 10% fetal bovine serum (FBS), penicillin/streptomycin, and 5% CO₂ at 37°C. Treatment options for HCC cells include 0.1% DMSO, 2.5 μM, 5 μM, 10 μM, 20 μM XAV-939 or G007-LK, either by itself or in combination with the AKT inhibitor MK-2206 (5 μM) or the MEK inhibitor U0126 (25 μM). The Cell Death Detection Elisa Plus Kit is used to measure apoptosis, and the BrdU Cell Proliferation Assay Kit is used to analyze cell proliferation[3].

Animal Protocol

Unless specifically noted, Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice, either single or double transgenic, are used in drug treatment experiments. G007-LK is given orally in two ways: either as a 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 as an enriched chow (100 or 1000 mg G007-LK/kg chow ad libitum). This corresponds to a daily G007-LK dose of roughly 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 administered for 9 or 21 days, starting at 5 weeks and 5 days for oral gavage treatment and 6 weeks for the administration of enriched chow, respectively[2].

References

[1]. 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]. 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]. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One. 2017 Sep 6;12(9):e0184068.

Solubility Data

Solubility (In Vitro)

DMSO: 69~100 mg/mL (130.2~188.7 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: 2.08 mg/mL (3.92 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.08 mg/mL (3.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.8869 mL	9.4347 mL	18.8693 mL
	5 mM	0.3774 mL	1.8869 mL	3.7739 mL
	10 mM	0.1887 mL	0.9435 mL	1.8869 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

G007-LK 1380672-07-0

CAS No.: 1380672-07-0

Physicochemical Properties

Biological Activity

Solubility Data