réservé à la recherche

Tariquidar (XR9576) P-gp inhibiteur

N° Cat.S8028

Tariquidar est un inhibiteur non compétitif puissant et sélectif de la P-glycoprotéine avec un Kd de 5,1 nM dans la lignée cellulaire CHrB30, il inverse la résistance aux médicaments dans les lignées cellulaires MDR. Phase 3.
Tariquidar (XR9576) P-gp inhibiteur Chemical Structure

Structure chimique

Poids moléculaire: 646.73

Aller à

Contrôle qualité

Lot : Pureté : 99.81%
99.81

Culture cellulaire, traitement et concentration de travail

Lignées cellulaires Type dessai Concentration Temps dincubation Formulation Description de lactivité PMID
K562/DOX Function assay 1 uM 10 mins Inhibition of P-gp in human K562/DOX cells assessed as increase in rhodamine-123 efflux in human K562 cells at 1 uM incubated for 10 mins hrs by flow cytometry relative to untreated control 28113128
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
KB-V1 Function assay 200 nM Inhibition of P-gp in human KB-V1 cells assessed as increase in rhodamine 123 accumulation at 200 nM 21657271
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
HepG2 Cytotoxicity assay 48 hrs Cytotoxicity against adriamycin-resistant human HepG2 cells assessed as inhibition of cell proliferation after 48 hrs by MTT assay, IC50=37.2μM 27328029
K562 Cytotoxicity assay 48 hrs Cytotoxicity against human K562 cells after 48 hrs by MTT assay, IC50=31.56μM 28645831
K562 Cytotoxicity assay 48 hrs Cytotoxicity against human K562 cells assessed as reduction in cell viability after 48 hrs by MTT assay, IC50=31.56μM 29631786
A2780adr Function assay 10 uM 30 mins Inhibition of ABCB1 in human A2780adr cells assessed as increase in accumulation of calcein AM at 10 uM preincubated for 30 mins followed by calcein AM addition measured every 60 secs for 60 mins by fluorescence assay relative to control 29547272
K562/A02 Cytotoxicity assay 48 hrs Cytotoxicity against human K562/A02 cells overexpressing P-gp assessed as reduction in cell viability after 48 hrs by MTT assay, IC50=27.19μM 29631786
CCD-18Co Cytotoxicity assay 48 hrs Cytotoxicity against human CCD-18Co cells assessed as cell viability after 48 hrs by MTT assay, IC50=25μM 26197160
SW620/AD300 Cytotoxicity assay 48 hrs Cytotoxicity against human SW620/AD300 cells assessed as cell viability after 48 hrs by MTT assay, IC50=25μM 26197160
HLF Cytotoxicity assay 48 hrs Cytotoxicity against HLF cells assessed as inhibition of cell proliferation after 48 hrs by MTT assay, IC50=16.69μM 27328029
CEM/VLB500 Growth inhibition assay 3 days Growth inhibition of human CEM/VLB500 cells after 3 days by resazurin assay, GI50=13.5μM 17399990
MCF7/ADR Cytotoxicity assay 48 hrs Intrinsic cytotoxicity against human MCF7/ADR cells assessed as inhibition of cell proliferation after 48 hrs by MTT assay, IC50=13.1μM 27328029
HCT116 Cytotoxicity assay 48 hrs Cytotoxicity against human HCT116 cells assessed as cell viability after 48 hrs by MTT assay, IC50=12.5μM 26197160
K562/A02 Function assay 48 hrs Inhibition of ABCB1 in human K562/A02 cells assessed as potentiation of adriamycin-induced cytotoxicity by measuring ADR IC50 treated for 48 hrs followed by compound washout measured after 12 hrs by MTT assay (Rvb = 51.34 +/- 5.1 uM), IC50=8.28μM 28645831
KBV Function assay 5 uM 72 hrs Reversal of P-gp-mediated drug resistance in human KBV cells assessed as potentiation of cytotoxicity by measuring IC50 at 5 uM after 72 hrs by MTT assay (Rvb = 398.34 +/- 0.58 uM), IC50=5.24μM 30384042
K562/A02 Function assay 48 hrs Inhibition of ABCB1 in human K562/A02 cells assessed as potentiation of adriamycin-induced cytotoxicity by measuring ADR IC50 treated for 48 hrs followed by compound washout measured after 6 hrs by MTT assay (Rvb = 51.34 +/- 5.1 uM), IC50=4.97μM 28645831
KBV Function assay 10 uM 72 hrs Reversal of P-gp-mediated drug resistance in human KBV cells assessed as potentiation of cytotoxicity by measuring IC50 at 10 uM after 72 hrs by MTT assay (Rvb = 398.34 +/- 0.58 uM), IC50=4.46μM 30384042
K562/A02 Function assay 48 hrs Inhibition of ABCB1 in human K562/A02 cells assessed as potentiation of adriamycin-induced cytotoxicity by measuring ADR IC50 treated for 48 hrs followed by compound washout measured immediately by MTT assay (Rvb = 51.34 +/- 5.1 uM), IC50=3.02μM 28645831
K562/A02 Function assay 5 uM 48 hrs Inhibition of ABCB1 in human K562/A02 cells assessed as potentiation of adriamycin-induced cytotoxicity by measuring ADR IC50 at 5 uM measured after 48 hrs by MTT assay (Rvb = 43.75 to 96.91 uM), IC50=1.97μM 28645831
K562/A02 Function assay 48 hrs Inhibition of ABCB1 in human K562/A02 cells assessed as potentiation of adriamycin-induced cytotoxicity by measuring ADR IC50 measured after 48 hrs by MTT assay (Rvb = 51.34 +/- 5.1 uM), IC50=1.6μM 28645831
MCF-7 MX Function assay Inhibition of BCRP expressed in MCF-7 MX cells using Hoechst 33342 staining, IC50=1.5μM 21354800
MCF7 Function assay Inhibition of ABCG2 in human mitoxantrone-resistant MCF7 cells by Hoechst 33342 assay, IC50=1.44544μM 18678495
HFE Cytotoxicity assay 72 hrs Cytotoxicity against human HFE cells assessed as cell viability after 72 hrs by MTT assay, IC50=1.28μM 26197160
MDCK Function assay Inhibition of BCRP expressed in MDCK cells using Hoechst 33342 staining, IC50=0.94μM 21354800
MCF7/Topo Function assay Inhibition of ABCG2 overexpressed in human MCF7/Topo cells by flow cytometric-based mitoxantrone efflux assay, IC50=0.916μM 19170519
MCF7/Topo Function assay 2 hrs Inhibition of ABCG2 in human MCF7/Topo cells after 2 hrs by Hoechst 33342 staining based fluorescence assay, IC50=0.526μM 30128080
MCF7/Topo Function assay 2 hrs Inhibition of ABCG2 in human MCF7/Topo cells after 2 hrs by Hoechst 33342 microplate assay, IC50=0.526μM 24900683
MCF7/Topo Function assay Inhibition of ABCG2 expressed in human MCF7/Topo cells by Hoechst microplate assay, IC50=0.526μM 21570282
MCF7/Topo Function assay Inhibition of ABCG2 in human MCF7/Topo cells by Hoechst 33342 assay, IC50=0.52μM 26774038
KBV1 Function assay 10 mins Inhibition of ABCB1 in human KBV1 cells after 10 mins by Calcein-AM microplate assay, IC50=0.223μM 24900683
Kb-V1 Function assay 10 mins Inhibition of ABCB1 expressed in Kb-V1 cells after 10 mins by calcein-AM assay, IC50=0.223μM 21570282
KBv1 Function assay Inhibition of ABCB1 overexpressed in human KBv1 cells by flow cytometric-based calcein-AM efflux assay, IC50=0.223μM 19170519
KBV1 Function assay Inhibition of ABCB1 in human KBV1 cells assessed as inhibition of calcein-AM efflux, IC50=0.22μM 26774038
A2780 Function assay 30 mins Inhibition of human Pgp in A2780 cells after 30 mins by Hoechst 33342 assay, IC50=0.12589μM 18083034
KB-3-1 Function assay 1000 nM 72 hrs Potentiation of doxorubicin-induced cytotoxicity against human KB-3-1 cells assessed as doxorubicin IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 0.15 +/- 0.04 uM), IC50=0.11μM 27504669
OVCAR8 Function assay 1000 nM 72 hrs Potentiation of doxorubicin-induced cytotoxicity against human OVCAR8 cells assessed as doxorubicin IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 0.12 +/- 0.03 uM), IC50=0.08μM 27504669
A2780/ADR Function assay Inhibition of P-glycoprotein-mediated multidrug resistance in adriamycin-resistant human A2780/ADR cells by calcein AM assay, IC50=0.078μM 19250834
A2780adr Function assay Inhibition of P-gp expressed in A2780adr cells by calcein AM accumulation assay, IC50=0.08μM 21354800
A2780 Function assay Inhibition of P-gp in human adriamycin-resistant A2780 cells by Hoechst 33342 assay, IC50=0.07244μM 18678495
KBV1 Function assay 1000 nM 72 hrs Inhibition of human ABCB1 expressed in KBV1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring doxorubicin IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 5.07 +/- 0.19 uM), IC50=0.07μM 27504669
CEM/VLB500 Function assay 3 days Reversal of P-gp-mediated multidrug resistance to in human CEM/VLB500 cells after 3 days by resazurin assay, EC50=0.068μM 17399990
EMT6/AR1.0 Function assay 1 hr Inhibition of mouse Pgp in EMT6/AR1.0 cells after 1 hr by daunorubicin accumulation assay, IC50=0.06457μM 18083034
EMT6/AR1.0 Function assay 1 hr Inhibition of mouse Pgp in EMT6/AR1.0 cells after 1 hr by daunorubicin accumulation assay, IC50=0.064μM 18083034
MDCK Function assay 30 mins Inhibition of P-glycoprotein (unknown origin) expressed in MDCK cells assessed as reduction of calcein-AM transport after 30 mins by fluorescence assay, EC50=0.044μM 24607999
MDCK Function assay 30 mins Activity at MDR1 (unknown origin) expressed in MDCK cells using calcein AM as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by fluorometric analysis, EC50=0.044μM 23374872
NCI-ADR-RES Function assay 1000 nM 72 hrs Inhibition of human ABCB1 expressed in NCI-ADR-RES cells assessed as potentiation of cytotoxicity by measuring IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 3714.80 +/- 383.58 nM), IC50=0.01851μM 27504669
KBV1 Function assay 1000 nM 72 hrs Inhibition of human ABCB1 expressed in KBV1 cells assessed as potentiation of cytotoxicity by measuring IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 277.68 +/- 56.61 nM), IC50=0.00066μM 27504669
HEK293 Function assay 1000 nM 72 hrs Potentiation of doxorubicin-induced cytotoxicity against HEK293 cells assessed as doxorubicin IC50 at 1000 nM after 72 hrs by CCK8 assay (Rvb = 5.28 +/- 0.74 nM), IC50=0.00495μM 27504669
K562/A02 Cytotoxicity assay 48 hrs Cytotoxicity against human K562/A02 cells after 48 hrs by MTT assay, IC50=27.19μM 28645831
SW620 Cytotoxicity assay 48 hrs Cytotoxicity against human SW620 cells assessed as cell viability after 48 hrs by MTT assay, IC50=25μM 26197160
K562/A02 Function assay 48 hrs Inhibition of ABCB1 in human K562/A02 cells assessed as potentiation of adriamycin-induced cytotoxicity by measuring ADR IC50 treated for 48 hrs followed by compound washout measured after 24 hrs by MTT assay (Rvb = 51.34 +/- 5.1 uM), IC50=14.39μM 28645831
MDCK Function assay Inhibition of BCRP expressed in MDCK cells by pheophorbide A assay, IC50=0.85μM 19932960
MCF7 MX Function assay Inhibition of BCRP expressed in MCF7 MX cells by Hoechst 33342 staining, IC50=0.68μM 19932960
NCI-ADR-RES Function assay 1000 nM 72 hrs Inhibition of human ABCB1 expressed in NCI-ADR-RES cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring doxorubicin IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 5.54 +/- 0.60 uM), IC50=0.24μM 27504669
MDCK Function assay Inhibition of MDR1 expressed in MDCK cells using rhodamine 123 staining by flow cytometry, IC50=0.21μM 21354800
CCRF-CEM/VCR1000 Function assay 240 secs Inhibition of P-glycoprotein-mediated daunorubicin efflux from human CCRF-CEM/VCR1000 cells after 240 secs by FACS flow cytometric analysis, IC50=0.03311μM 22452412
HEK293 Function assay 1000 nM 72 hrs Inhibition of human ABCB1 transfected in HEK293 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring doxorubicin IC50 at 1000 nM after 72 hrs by CCK8 assay (Rvb = 504.65 +/- 44.94 nM), IC50=0.02477μM 27504669
KB-3-1 Function assay 1000 nM 72 hrs Potentiation of cytotoxicity against human KB-3-1 cells assessed as IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 0.78 +/- 0.27 nM), IC50=0.00041μM 27504669
OVCAR8 Function assay 1000 nM 72 hrs Potentiation of cytotoxicity against human OVCAR8 cells assessed as IC50 at 1000 nM after 72 hrs by MTT assay (Rvb = 8.53 +/- 1.95 nM), IC50=0.00518μM 27504669
MDCK Function assay 30 mins Activity at BCRP (unknown origin) expressed in MDCK cells using rhodamine 123 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by fluorometric analysis, EC50=0.01μM 23374872
HepG2 Function assay 10 uM 90 mins Inhibition of P-gp mediated efflux in adriamycin-resistant human HepG2 cells assessed as intracellular rhodamine-123 accumulation at 10 uM incubated in dark condition for 90 mins by flow cytometry relative to control 27328029
Cliquez pour voir plus de données expérimentales sur les lignées cellulaires

Informations chimiques, stockage et stabilité

Poids moléculaire 646.73 Formule

C38H38N4O6

Stockage (À partir de la date de réception)
N° CAS 206873-63-4 Télécharger le SDF Stockage des solutions mères

Synonymes XR9576 Smiles COC1=C(C=C2CN(CCC2=C1)CCC3=CC=C(C=C3)NC(=O)C4=CC(=C(C=C4NC(=O)C5=CC6=CC=CC=C6N=C5)OC)OC)OC

Solubilité

In vitro
Lot:

DMSO : 8 mg/mL (12.36 mM)
(Le DMSO contaminé par lhumidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Water : Insoluble

Ethanol : Insoluble

Calculateur de molarité

Masse Concentration Volume Poids moléculaire
Calculateur de dilution Calculateur de poids moléculaire

In vivo
Lot:

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Entrez les informations ci-dessous (Recommandé : Un animal supplémentaire pour tenir compte des pertes pendant lexpérience)

mg/kg g μL

Étape 2 : Entrez la formulation in vivo (Ceci nest que le calculateur, pas la formulation. Veuillez nous contacter dabord sil ny a pas de formulation in vivo dans la section Solubilité.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Résultats du calcul :

Concentration de travail : mg/ml;

Méthode de préparation du liquide maître DMSO : mg médicament prédissous dans μL DMSO ( Concentration du liquide maître mg/mL, Veuillez nous contacter dabord si la concentration dépasse la solubilité du DMSO du lot de médicament. )

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, ajouter ensuiteμL PEG300, mélanger et clarifier, ajouter ensuiteμL Tween 80, mélanger et clarifier, ajouter ensuite μL ddH2O, mélanger et clarifier.

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, ajouter ensuite μL Huile de maïs, mélanger et clarifier.

Remarque : 1. Assurez-vous que le liquide est clair avant dajouter le solvant suivant.
2. Assurez-vous dajouter le(s) solvant(s) dans lordre. Vous devez vous assurer que la solution obtenue lors de lajout précédent est une solution claire avant de procéder à lajout du solvant suivant. Des méthodes physiques telles que le vortex, les ultrasons ou le bain-marie peuvent être utilisées pour faciliter la dissolution.

Mécanisme daction

Targets/IC50/Ki
P-gp
(CHrB30 cells)
5.1 nM(Kd)
In vitro

Tariquidar présente une liaison de haute affinité à la P-gp avec une Bmax de 275 pmol/mg. Ce composé montre une interaction non compétitive avec les substrats de la P-gp. Il augmente l'accumulation à l'état d'équilibre de ces cytotoxiques dans les cellules CHrB30 à des niveaux observés dans les cellules AuxB1 n'exprimant pas de P-gp avec une CE50 de 487 nM. Cette substance chimique est capable d'inhiber l'activité ATPasique de la P-gp sensible au vanadate de 60 à 70%, avec des valeurs de CI50 puissantes de 43 nM. Il peut inhiber d'autres mécanismes de résistance à des concentrations plus élevées. 1 μM de ce composé abroge la résistance médiée par ABCG2 (BCRP) aux camptothécines in vitro. Il potentialise la cytotoxicité de plusieurs médicaments, y compris la doxorubicine; une inversion complète de la résistance est obtenue en présence de 25 à 80 nM de ce produit chimique. Dans MC26, une lignée cellulaire de carcinome du côlon murin avec une chimiorésistance intrinsèque, la CI50 de la doxorubicine est cinq fois inférieure en présence de 0,1 μM de ce composé (36 vs 7 nM). Dans les lignées cellulaires de carcinome mammaire murin, de carcinome pulmonaire à petites cellules humain et de carcinome ovarien humain avec une résistance chimithérapeutique acquise (EMT6/AR1.0, H69/LX4 et 2780 AD), la CI50 in vitro de la doxorubicine est 22 à 150 fois inférieure en présence de 0,1 μM de ce produit chimique. L'inhibition de la P-gp persiste pendant 23 h après son retrait du système de culture. Il a restauré la cytotoxicité de la doxorubicine dans le modèle de sphéroïde tumoral multicellulaire National Cancer Institute (NCI)/ADRRES dérivé de la lignée cellulaire de cancer du sein MCF7WT.

Kinase Assay
Test d'accumulation de médicaments à l'état d'équilibre
Les cellules sont incubées dans un volume de réaction de 1 mL pendant 60 min à 37 ℃ sous 5 % de CO2 afin d'atteindre l'état d'équilibre. L'effet des modulateurs XR9576 sur l'accumulation de [3H]-ligand est étudié dans la plage de concentration 10-9 - 10-6 M. Ce composé est ajouté à partir d'une solution mère de DMSO donnant une concentration finale de solvant de 0,2 % (v/v). Après la récolte des cellules, le médicament accumulé est mesuré par comptage par scintillation liquide et normalisé pour la teneur en protéines cellulaires. Les tracés de la quantité accumulée en fonction de la concentration du modulateur sont ajustés avec l'équation générale dose-réponse : Y={(a-b)/(1+(X/c)d)}+bOù : Y=réponse ; a=réponse initiale ; b=réponse finale ; c=concentration EC50 ; d=valeur de la pente ; X=concentration du médicament.
In vivo

Tariquidar (2-8 mg/kg p.o.) s'est avéré potentialiser significativement l'activité antitumorale de la doxorubicine (5 mg/kg, i.v.) contre le carcinome murin du côlon MC26 in vivo. Dans les xénogreffes de carcinome humain, la coadministration de ce composé (6-12 mg/kg p.o.) a entièrement restauré l'activité antitumorale contre deux xénogreffes de tumeurs humaines MDR hautement résistantes (2780AD, H69/LX4) chez des souris nues.

Références
  • [4] https://pubmed.ncbi.nlm.nih.gov/14962729/

Applications

Méthodes Biomarqueurs Images PMID
Immunofluorescence MRP7
S8028-IF1
23393594

Informations sur lessai clinique

(données de https://clinicaltrials.gov, mis à jour le 2024-05-22)

Numéro NCT Recrutement Conditions Sponsor/Collaborateurs Date de début Phases
NCT01663545 Completed
Epilepsies Partial
National Institute of Neurological Disorders and Stroke (NINDS)|National Institutes of Health Clinical Center (CC)
July 31 2012 --
NCT01547754 Terminated
HIV-Associated Cognitive Motor Complex
National Institute of Mental Health (NIMH)|National Institutes of Health Clinical Center (CC)
January 9 2012 --
NCT01386476 Completed
Drug Resistance
National Institute of Mental Health (NIMH)|National Institutes of Health Clinical Center (CC)
June 15 2011 --
NCT00082368 Completed
Cancer
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)
May 16 2004 Phase 2

Support technique

Instructions de manipulation

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

Si vous avez dautres questions, veuillez laisser un message.

Veuillez entrer votre nom.
Veuillez entrer votre e-mail. Veuillez entrer une adresse e-mail valide.
Veuillez nous écrire quelque chose.

Questions fréquemment posées

Question 1:
Can you please give me more specific and detailed information of how to dissolve and use it (S8028) for in vivo studies?

Réponse :
It in 30% Propylene glycol, 5% Tween 80, 65% D5W at 30mg/ml will be a suspension or emulsion. If you are going to administrate this compound by oral gavage, it is fine. We also have test some vehicles for it for i.p injection, and it is soluble in 5% DMSO+45% PEG 300+ddH2O at 2mg/ml clearly. When preparing the solution, please dissolve it in DMSO clearly first, then add PEG. After they mixed well, then dilute with water.