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| Targets |
The primary target of K-756 is tankyrase (TNKS1 and TNKS2), also known as PARP5, a member of the PARP family. Tankyrase regulates the stability of AXIN, a scaffold protein that facilitates the phosphorylation and degradation of β-catenin. By inhibiting tankyrase, K-756 stabilizes AXIN, which enhances the formation of the β-catenin destruction complex and promotes the degradation of β-catenin. K-756 is a direct and selective TNKS inhibitor with IC₅₀ values of 31 nM and 36 nM for TNKS1 and TNKS2, respectively. It binds to the induced pocket of TNKS and inhibits its enzyme activity.
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| ln Vitro |
Tankyrase (TNKS) is the target of K-756, a new selective inhibitor of the Wnt/β-catenin pathway. TNKS belongs to the PARP family (paramp5, if you will). K-756 binds to TNKS's inducible pocket and stops the enzyme from active. The inhibitory activity of the PARP family enzyme at 10 μM was assessed in order to investigate the isoform selectivity of K-756. TNKS1 and TNKS2 are 97% and 100% inhibited, respectively, by K-756. On the other hand, K-756 had less than 13% of its inhibitory action against PARP1, PARP2, PARP3, PARP6, PARP7, and PARP11. By blocking the Wnt/β-catenin pathway, K-756 prevents the proliferation of APC mutant colorectal cancer COLO 320DM and SW403 cells. With an IC50 of 110 nM, K-756 significantly suppresses reporter gene activity in DLD-1/TCF-Luc cells, but not in DLD-1/mtTCF-Luc cells, not even at 1,000 nM. Following a 144-hour treatment with K-756, the APC mutant colorectal cancer cell lines COLO 320DM and SW403 cells were assessed for cell growth suppression using the XTT assay. K-756 was applied, and at a GI50 of 780 nM, it stopped COLO 320DM cells from growing. K-756 has a GI50 of 270 nM and inhibits SW403 as well[1].
In vitro, K-756 inhibits the ADP-ribosylation activity of TNKS1 and TNKS2 with IC₅₀ values of 31 nM and 36 nM, respectively. It inhibits the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/β-catenin pathway. By inhibiting TNKS, K-756 stabilizes AXIN and promotes β-catenin degradation, leading to reduced Wnt target gene transcription. The compound's selectivity for TNKS makes it a valuable tool for studying Wnt signaling. |
| ln Vivo |
DLD-1/TCF-Luc cell xenografts were produced in SCID mice. Vehicle (0.5% MC400) or K-756 was delivered orally once day for 3 days at dosages of 100, 200, and 400 mg/kg. Inhibition of Wnt/β-catenin signaling in tumors was examined by measuring FGF20 and LGR5 as well as luciferase activity. The expression and reporter gene activity of FGF20 were significantly reduced after 3 days of administration at doses of 100 mg/kg and above. The expression of LGR5 was dramatically reduced when supplied for 3 days at dosages of 200 mg/kg and higher. K-756 achieved maximum inhibitory activity at a dosage of 400 mg/kg for 3 days. Inhibition of Wnt/β-catenin signaling was observed at a dose of 400 mg/kg 1 day after dosing [1].
In vivo, K-756 is studied in the context of metabolic disorders such as type 2 diabetes, dyslipidemia, and atherosclerosis. Through its receptor-modulating action, it helps regulate gene expression related to energy balance and glucose metabolism. The compound's ability to inhibit Wnt/β-catenin signaling suggests potential applications in cancer and metabolic diseases. However, specific in vivo efficacy data from animal models is not detailed in the available sources. |
| Enzyme Assay |
For tankyrase inhibitors, standard cell-free assays involve measuring the PARP (poly ADP-ribose polymerase) activity of recombinant tankyrase 1/2. The compound is incubated with the enzyme and NAD⁺, and PARylation activity is measured by incorporation of biotin-NAD⁺ or by ELISA to determine IC₅₀ values.
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| Cell Assay |
For Wnt/β-catenin inhibitors, standard cellular assays use cells with a Wnt-responsive luciferase reporter. Cells are treated with the test compound, and luciferase activity is measured. AXIN and β-catenin levels are measured by western blot. Cell proliferation is assessed in cancer cell lines.
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| Animal Protocol |
For in vivo evaluation of Wnt/β-catenin inhibitors, standard animal models include tumor xenograft models of colorectal cancer and metabolic disease models (type 2 diabetes, dyslipidemia). The compound is typically administered orally, and tumor growth, metabolic parameters, and Wnt target gene expression are assessed.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for K-756 is not extensively provided in the available sources. The compound has a molecular weight of 335.16 and formula C₂₃H₂₃N₅O₃. It is soluble in DMSO at 5 mg/mL (warmed). As a small molecule with moderate lipophilicity, it would be expected to have reasonable cell permeability and oral bioavailability. Comprehensive PK studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
Detailed toxicology data for K-756 is not provided in the available sources. As a research compound targeting tankyrase and Wnt signaling, standard preclinical toxicology would be required for therapeutic development. The compound's effects on normal Wnt signaling in various tissues would need to be evaluated. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
K-756 is a novel and selective Wnt/β-catenin pathway inhibitor targeting tankyrase (TNKS). It inhibits TNKS1 and TNKS2 with IC₅₀ values of 31 nM and 36 nM, respectively. The compound inhibits the cell growth of APC-mutant colorectal cancer cells. It has the molecular formula C₂₃H₂₃N₅O₃. No regulatory approval has been identified.
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| Molecular Formula |
C24H27N5O3
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| Molecular Weight |
433.502885103226
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| Exact Mass |
433.211
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| CAS # |
130017-40-2
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| PubChem CID |
14668434
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| Appearance |
White to off-white solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
643
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1NC2C=CC=CC=2CN1CC1CCN(C2C3C=C(C(=CC=3N=CN=2)OC)OC)CC1
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| InChi Key |
GWXCGEJJQFHPPA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H27N5O3/c1-31-21-11-18-20(12-22(21)32-2)25-15-26-23(18)28-9-7-16(8-10-28)13-29-14-17-5-3-4-6-19(17)27-24(29)30/h3-6,11-12,15-16H,7-10,13-14H2,1-2H3,(H,27,30)
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| Chemical Name |
3-[[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl]-1,4-dihydroquinazolin-2-one
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| Synonyms |
K756; K 756; K-756
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ~4.55 mg/mL (~10.50 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.46 mg/mL (1.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 4.6 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: ≥ 0.46 mg/mL (1.06 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 4.6 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 0.45 mg/mL (1.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3068 mL | 11.5340 mL | 23.0681 mL | |
| 5 mM | 0.4614 mL | 2.3068 mL | 4.6136 mL | |
| 10 mM | 0.2307 mL | 1.1534 mL | 2.3068 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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