NVP-TNKS656

TNKS2 inhibitor CAS# 1419949-20-4

NVP-TNKS656

Catalog No. BCC6541----Order now to get a substantial discount!

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Chemical structure

NVP-TNKS656

3D structure

Chemical Properties of NVP-TNKS656

Cas No. 1419949-20-4 SDF Download SDF
PubChem ID 71227201 Appearance Powder
Formula C27H34N4O5 M.Wt 494.58
Type of Compound N/A Storage Desiccate at -20°C
Synonyms TNKS656
Solubility DMSO : ≥ 40 mg/mL (80.88 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-(cyclopropylmethyl)-2-[4-(4-methoxybenzoyl)piperidin-1-yl]-N-[(4-oxo-1,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-2-yl)methyl]acetamide
SMILES COC1=CC=C(C=C1)C(=O)C2CCN(CC2)CC(=O)N(CC3CC3)CC4=NC(=O)C5=C(N4)CCOC5
Standard InChIKey DYGBNAYFDZEYBA-UHFFFAOYSA-N
Standard InChI InChI=1S/C27H34N4O5/c1-35-21-6-4-19(5-7-21)26(33)20-8-11-30(12-9-20)16-25(32)31(14-18-2-3-18)15-24-28-23-10-13-36-17-22(23)27(34)29-24/h4-7,18,20H,2-3,8-17H2,1H3,(H,28,29,34)
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 NVP-TNKS656

DescriptionNVP-TNKS656 is a highly potent, selective, and orally active TNKS2 inhibitor with IC50 of 6 nM, and is > 300 fold selectivity against PARP1 and PARP2.In Vivo:NVP-TNKS656 (30 or 100 mg/kg, p.o.) exhibits good exposure and moderate oral bioavailability of 32% and 53%, respectively. Some slight overproportional increase in oral exposure is observed between 30 and 100 mg/kg with the dose normalized AUC for the 100 mg/kg dose being 2-fold higher than for the 30 mg/kg dose. Mice treated with NVP-TNKS656 (350 mg/kg, p.o.) show good plasma and tumor exposures corresponding to AUC0-24h of 515 and 325 μM·h, respectively[1].

References:
[1]. Shultz MD, et al. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J Med Chem. 2013 Aug 22;56(16):6495-511.

Protocol

Animal Administration [1]
Athymic female nude mice weighing 19-22 g are implanted subcutaneously with a 3×3×3 mm3 tumor fragment from an MMTV-Wnt1 tumor-bearing mouse. Tumors are grown to approximately 250-300 mm3. Individual mice are given a single oral dose of vehicle (n=3) (4% HCl:10% propylene glycol:20% Solutol HS15:60.5% D5W:0.5% NaOH) or TNKS656 at 350 mg/kg (n=18). At 0.5, 1, 2, 4, 8, 16, or 24 h following dosing (n=3/time point), mice are euthanized, and blood is collected via cardiac puncture and processed for plasma. Tumors are excised from mice and frozen at −80°C for PD analysis.

References:
[1]. Shultz MD, et al. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J Med Chem. 2013 Aug 22;56(16):6495-511.

NVP-TNKS656 Dilution Calculator

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NVP-TNKS656 Molarity Calculator

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Preparing Stock Solutions of NVP-TNKS656

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0219 mL 10.1096 mL 20.2192 mL 40.4384 mL 50.5479 mL
5 mM 0.4044 mL 2.0219 mL 4.0438 mL 8.0877 mL 10.1096 mL
10 mM 0.2022 mL 1.011 mL 2.0219 mL 4.0438 mL 5.0548 mL
50 mM 0.0404 mL 0.2022 mL 0.4044 mL 0.8088 mL 1.011 mL
100 mM 0.0202 mL 0.1011 mL 0.2022 mL 0.4044 mL 0.5055 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 NVP-TNKS656

NVP-TNKS656 has been identified as an orally active antagonist of Wnt pathway activity. The Wnt pathway has been involved in controlling numerous developmental processes. Deregulation of this pathway may result in carcinogenesis [1].

In vitro: The IC50 value of NVP-TNKS656 against TNKS2, PARP1, PARP2, and STF was 0.006, > 19, 32, and 0.0035 ?M, respectively [1].

In vivo: After intravenous administration in mice, the clearance and volume of distribution of NVP-TNKS656 were 10 mL/min/kg and 0.6 L/kg, respectively. The exposure and oral bioavailability was 32% and 53%, respectively. In the mouse mammary tumor virus (MMTV)-Wnt1 transgenic model, NVP-TNKS656 could activate the Wnt signaling after oral administration of NVP-TNKS656 at a dose of 350 mg/kg over a 24-h time course. NVP-TNKS656 treated tumors exhibited 70?80% reduction in the Wnt/beta-catenin target gene Axin2 mRNA level [1].

Reference:
Shultz M D, Cheung A K, Kirby C A, et al.  Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor[J]. Journal of medicinal chemistry, 2013, 56(16): 6495-6511.

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References on NVP-TNKS656

Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor.[Pubmed:23844574]

J Med Chem. 2013 Aug 22;56(16):6495-511.

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.

Description

NVP-TNKS656 is a highly potent, selective, and orally active TNKS2 inhibitor with IC50 of 6 nM, and is > 300 fold selectivity against PARP1 and PARP2.

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