Tariquidar

Catalog No.S8028

Tariquidar is a potent and selective noncompetitive inhibitor of P-glycoprotein with Kd of 5.1 nM in CHrB30 cell line, reverses drug resistance in MDR cell Lines. Phase 3.

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Tariquidar Chemical Structure

Tariquidar Chemical Structure
Molecular Weight: 646.73

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Product Description

Biological Activity

Description Tariquidar is a potent and selective noncompetitive inhibitor of P-glycoprotein with Kd of 5.1 nM in CHrB30 cell line, reverses drug resistance in MDR cell Lines. Phase 3.
Targets P-gp [1]
(CHrB30 cells)
IC50 5.1 nM(Kd)
In vitro Tariquidar displays high-affinity binding to P-gp with Bmax of 275 pmol/mg. Tariquidar shows non-competitive interaction with the P-gp substrates vinblastine and paclitaxel. Tariquidar increases the steady-state accumulation of these cytotoxics in CHr<>/supB30 cells to levels observed in non-P-gp-expressing AuxB1 cells with EC50 of 487 nM. Tariquidar is able to inhibit the vanadate-sensitive ATPase activity of P-gp by 60-70%, with potent IC50 values of 43 nM. [1] Tariquidar may inhibit other resistance mechanisms at higher concentrations. 1 μM Tariquidar abrogates ABCG2 (BCRP)-mediated resistance to camptothecins in vitro. [2] Tariquidar potentiates the cyto-toxicity of several drugs including doxorubicin, paclitaxel, etoposide, and vincristine; complete reversal of resistance is achieved in the presence of 25- 80 nM Tariquidar. In MC26, a murine colon carcinoma cell line with intrinsic chemoresistance, the doxorubicin IC50 is fivefold lower in the presence of 0.1 μM Tariquidar (36 vs 7 nM). In murine mammary carcinoma, human small-cell lung carcinoma and human ovarian carcinoma cell lines with acquired chemotherapeutic resistance (EMT6/AR1.0, H69/LX4 and 2780 AD), the in vitro doxorubicin IC50 is 22-150-fold lower in the presence of 0.1 μM Tariquidar. P-gp inhibition persists for 23 h after removal of Tariquidar from the culture system. [3] Tariquidar restored the cyto-toxicity of doxorubicin and vinblastine in the National Cancer Institute (NCI)/ADRRES multicellular tumor spheroid model derived from the MCF7WT breast cancer cell line. [4]
In vivo Tariquidar (2- 8 mg/kg p.o.) is found to significantly potentiate the antitumor activity of doxorubicin (5 mg/kg, i.v.) against MC26 murine colon carcinoma in vivo. In human carcinoma xenografts, coadministration of XR9576 (6 -12 mg/kg p.o.) fully restored the antitumor activity of paclitaxel, etoposide, and vincristine against two highly resistant MDR human tumor xenografts (2780AD, H69/LX4) in nude mice. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Steady-state drug accumulation assay AuxB1 and CHrB30 cells are grown to confluency in 12-well (24 mm) tissue culture dishes and the steady-state accumulation of [3H]-vinblastine is measured. Accumulation is initiated by the addition of 0.1 μ Ci [3H]-vinblastine and unlabelled vinblastine to a final concentration of 100 nM . The accumulation of [3H]-paclitaxel is measured using 0.1 μ Ci [3H]-paclitaxel and unlabelled drug to a final concentration of 1 μM . Cells are incubated in a reaction volume of 1 mL for 60 min at 37 ℃ under 5% CO2 in order to reach steady-state. The effect of the modulators XR9576 on [3H]-ligand accumulation is investigated in the concentration range 10-9 - 10-6 M. Modulators are added from a DMSO stock giving a final solvent concentration of 0.2 % (v/v). Following cell harvesting, accumulated drug is measured by liquid scintillation counting and normalized for cell protein content. Plots of amount accumulated as a function of modulator concentration are fitted with the general dose-response equation: Y={(a-b)/(1+(X/c)d)}+b Where: Y=response; a=initial response; b=final response; c=EC50 concentration; d=slope value; X=drug concentration.

Cell Assay: [3]

Cell lines Murine mammary carcinoma cell line MDR EMT6/AR1.0
Concentrations ~100 nM Tariquidar
Incubation Time 4 days
Method Cells are seeded into 96-well plates at 800/well, in 100 μL of medium and incubated for 4 h at 37 ℃. Varying concentrations of modulator or solvent control (50 μL/well) are subsequently added and incubated for an additional 1 h before the addition of the cytotoxic drug. The cytotoxic drug (50 μL) is added to give a range of final concentrations in quadruplicate wells. After incubation for an additional 4 days, cell proliferation of adherent cells is assessed using the sulforhodamine B assay.

Animal Study: [3]

Animal Models Murine colon carcinoma xenografts MC26
Formulation 5% (w/v) D-( 1)-glucose (dextrose) solution
Dosages 8 mg/kg
Administration Coadministration of Tariquidar (p.o.) with doxorubicin (5 mg/kg, i.v.)

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] Martin C, et al. Br J Pharmacol, 1999, 128(2), 403-411.

[2] Robey RW, et al. Cancer Res, 2004, 64(4), 1242-1246.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00082368 Completed Cancer National Cancer Institute (NCI)|National Institutes of He  ...more National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) May 2004 Phase 2
NCT00071058 Completed Adrenal Cortex Neoplasms National Cancer Institute (NCI)|National Institutes of He  ...more National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) October 2003 Phase 2
NCT00069160 Completed Lung Neoplasms|Ovarian Neoplasms|Cervix Neoplasms|Renal Neoplasms National Cancer Institute (NCI)|National Institutes of He  ...more National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) September 2003 Phase 2
NCT00042315 Terminated Stage IIIb Non-small Cell Lung Cancer|Stage IV Non-small Cell Lung Cancer QLT Inc. June 2002 Phase 3
NCT00042302 Terminated Stage IIIb Non-small Cell Lung Cancer|Stage IV Non-small Cell Lung Cancer QLT Inc. June 2002 Phase 3

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Chemical Information

Download Tariquidar SDF
Molecular Weight (MW) 646.73
Formula

C38H38N4O6

CAS No. 206873-63-4
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms XR9576
Solubility (25°C) * In vitro DMSO 52 mg/mL (80.4 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 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-Quinolinecarboxamide, N-[2-[[[4-[2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)ethyl]phenyl]amino]carbonyl]-4,5-dimethoxyphenyl]-

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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