TPCA-1

Catalog No.S2824

TPCA-1 is an inhibitor of IKK-2 with IC50 of 17.9 nM in a cell-free assay, inhibits NF-κB pathway, exhibits 22-fold selectivity over IKK-1.

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TPCA-1 Chemical Structure

TPCA-1 Chemical Structure
Molecular Weight: 279.29

Validation & Quality Control

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Quality Control & MSDS

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Product Description

Biological Activity

Description TPCA-1 is an inhibitor of IKK-2 with IC50 of 17.9 nM in a cell-free assay, inhibits NF-κB pathway, exhibits 22-fold selectivity over IKK-1.
Targets IKK2 [1]
(Cell-free assay)
IC50 17.9 nM
In vitro In a time-resolved fluorescence resonance energy transfer assay, TPCA-1 inhibits human IKK-2 activity with an IC50 of 17.9 nM. In addition, TPCA-1 is demonstrated to be ATP-competitive. Besides, TPCA-1 exhibits IC50 values of 400 nM and 3600 nM against IKK-1 and JNK3, respectively. TPCA-1 inhibits the production of TNF-α, IL-6, and IL-8 in a concentration-dependent manner, exhibiting IC50 values of 170, 290, and 320 nM, respectively. [1] TPCA-1 inhibits glioma cell proliferation, as well as TNF-induced RelA (p65) nuclear translocation and NFκB-dependent IL8 gene expression. Importantly, TPCA-1 inhibits IFN-induced gene expression, completely suppressing MX1 and GBP1 gene expression, while having only a minor effect on ISG15 expression. [2]
In vivo Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., results in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. are comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1beta, IL-6, TNF-alpha, and interferon-gamma, is significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo results in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduces the severity of CIA, as does etanercept administration at 12.5 mg/kg, i.p., every other day. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

IKK-2 Assay Recombinant human IKK-2 (residues 1-756) is expressed in baculovirus as an N-terminal GST-tagged fusion protein, and its activity is assessed using a time-resolved fluorescence resonance energy transfer assay. In brief, IKK-2 (5 nM final) diluted in assay buffer (50 mM HEPES, 10 mM MgCl2, 1 mM CHAPS, pH 7.4, with 1 mM DTT and 0.01% w/v BSA) is added to wells containing various concentrations of compound or dimethyl sulfoxide (DMSO) vehicle (3% final). The reaction is initiated by the addition of GST-IκBα substrate (25 nM final)/ATP (1 μM final), in a total volume of 30 μL. The reaction is incubated for 30 min at room temperature, then terminated by the addition of 15 μL of 50 mM EDTA. Detection reagent (15 μL) in buffer (100 mM HEPES, pH 7.4, 150 mM NaCl, and 0.1% w/v BSA) containing antiphosphoserine- IκBα-32/36 monoclonal antibody 12C2, labeled with W-1024 europium chelate, and an allophycocyanin-labeled anti-GST antibody is added, and the reaction is further incubated for 60 min at room temperature. The degree of phosphorylation of GST- IκBαis measured as a ratio of specific 665-nm energy transfer signal to reference europium 620-nm signal, using a Packard Discovery plate reader.

Cell Assay: [2]

Cell lines U87, MT330, SJ-G2, and GBM6 human glioma lines
Concentrations 0-50 μM
Incubation Time 3 days
Method Ten microliters of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) from stock solution (10 mg/mL) is added to each well of 96-well plates containing glioma cells and incubated at 37 °C for 2–4 h. Oxidized MTT is solubilized by adding 100 μL of 10% sodium dodecyl sulfate (SDS) in 0.01 N HCL, and plates are incubated at 37 °C for 4 h in a humidified chamber. Plates are read at 570 nm on a plate reader.

Animal Study: [1]

Animal Models Murine collagen-induced arthritis
Formulation 0.9% DMSO, 7% dimethylacetoacetamide (DMA), and 10% Cremophor El
Dosages 3, 10, or 20 mg/kg
Administration Administered via i.p. or b.i.d.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Podolin PL, et al, J Pharmacol Exp Ther, 2005, 312(1), 373-381.

[2] Du Z, et al, J Interferon Cytokine Res, 2012, 32(8), 368-377.

Chemical Information

Download TPCA-1 SDF
Molecular Weight (MW) 279.29
Formula

C12H10FN3O2

CAS No. 507475-17-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms GW683965
Solubility (25°C) * In vitro DMSO 56 mg/mL (200.5 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 2% Cremophor EL, 2% N,N-dimethylacetamide 15 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 3-Thiophenecarboxamide, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-

Customer Product Validation(2)


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Rating
Source Mol Cancer 2014 13, 40. TPCA-1 purchased from Selleck
Method Western blot
Cell Lines Human gastric adenocarcinoma cells
Concentrations 1 uM
Incubation Time 24 h
Results IL-1β-induced PTEN repression was attenuated in the presence of TPCA-1 or siRNAs for NF-kappaB.

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Rating
Source Exp Mol Med, 2015, 10.1038/emm.2015.37. TPCA-1 purchased from Selleck
Method Immunosorbent Assay
Cell Lines HUVECs
Concentrations 30 µM
Incubation Time 48 h
Results In addition, TPCA-1, an inhibitor of IKK-2, significantly suppressed the upregulation of PTX3 induced by PA (P<0.01).

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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