Home Protein Tyrosine Kinase VEGFR inhibitor Vandetanib (ZD6474)

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Vandetanib (ZD6474) VEGFR inhibitor

Kat.-Nr.: S1046

Vandetanib is a potent inhibitor of VEGFR2 with IC50 of 40 nM in a cell-free assay. It also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM. No activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM. Vandetanib (ZD6474) increases apoptosis and induces autophagy by increasing the level of reactive oxygen species (ROS).
Vandetanib (ZD6474) VEGFR inhibitor Chemical Structure

Chemische Struktur

Molekulargewicht: 475.35

Springe zu

Qualitätskontrolle (Quality Control)

Charge: Reinheit: 99.99%
99.99

Zellkultur, Behandlung & Arbeitskonzentration
(Cell Culture, Treatment & Working Concentration)

Zelllinien Assay-Typ Konzentration Inkubationszeit Formulierung Aktivitätsbeschreibung PMID
SN179  Function Assay 500 nM  16 h increases CXCR4 expression significantly 25676691
SN186 Function Assay 500 nM  16 h increases CXCR4 expression significantly 25676691
SN179  Function Assay 500 nM  16 h enhances the CXCL12 directed migration 25676691
SN179  Function Assay 500 nM  16 h increases basal migration  25676691
Jurkat Growth Inhibition Assay 72 h  GI50=1.5 ± 0.2 μM 24681205
K-562 Growth Inhibition Assay 72 h  GI50=1.8 ± 0.1 μM 24681205
NCTC-2544 Growth Inhibition Assay 72 h  GI50=4.6 ± 0.3 μM 24681205
A-431 Growth Inhibition Assay 72 h  GI50=2.4 ± 0.3 μM 24681205
SK-N-SH Growth Inhibition Assay 0.625-20 μM 48 h DMSO inhibits cell growth in a dose dependent manner 24399074
SH-SY5Y Growth Inhibition Assay 0.625-20 μM 48 h DMSO inhibits cell growth in a dose dependent manner 24399074
SK-N-SH Apoptosisi Assay 5/10/20 μM 48 h DMSO induces apoptosis dose dependently 24399074
SH-SY5Y Apoptosisi Assay 5/10/20 μM 48 h DMSO induces apoptosis dose dependently 24399074
SK-N-SH Function Assay 5/10/20 μM 48 h DMSO induces G1 phase cell cycle arrest 24399074
SH-SY5Y Function Assay 5/10/20 μM 48 h DMSO induces G1 phase cell cycle arrest 24399074
SK-N-SH Function Assay 1/5/10 μM 48 h DMSO inhibits RET phosphorylation 24399074
SH-SY5Y Function Assay 1/5/10 μM 48 h DMSO inhibits RET phosphorylation 24399074
SK-N-SH Function Assay 5/10 μM 48 h DMSO inhibits human NB cell migration 24399074
SH-SY5Y Function Assay 5/10 μM 48 h DMSO inhibits human NB cell migration 24399074
SK-N-SH Function Assay 5/10 μM 48 h DMSO inhibits human NB cell invasion 24399074
SH-SY5Y Function Assay 5/10 μM 48 h DMSO inhibits human NB cell invasion 24399074
SK-N-SH Function Assay 5 μM 24/48/72 h DMSO suppresses the expression of CXCR4 and MMP14 mRNA 24399074
SH-SY5Y Function Assay 5 μM 24/48/72 h DMSO suppresses the expression of CXCR4 and MMP14 mRNA 24399074
SK-N-SH Function Assay 5 μM 48/72 h DMSO suppresses expression of the CXCR4 and MMP14 protein 24399074
SH-SY5Y Function Assay 5 μM 48/72 h DMSO suppresses expression of the CXCR4 and MMP14 protein 24399074
HMEpC Growth Inhibition Assay 1 nM-100 μM 48 h  DMSO inhibits cell growth in a dose dependent manner 24138843
MCF-7 Growth Inhibition Assay 1 nM-100 μM 48 h  DMSO inhibits cell growth in a dose dependent manner 24138843
ZR-75-1 Growth Inhibition Assay 1 nM-100 μM 48 h  DMSO inhibits cell growth in a dose dependent manner 24138843
MDA-MB-231 Growth Inhibition Assay 1 nM-100 μM 48 h  DMSO inhibits cell growth in a dose dependent manner 24138843
MDA-MB-468 Growth Inhibition Assay 1 nM-100 μM 48 h  DMSO inhibits cell growth in a dose dependent manner 24138843
T-47-D Growth Inhibition Assay 1 nM-100 μM 48 h  DMSO inhibits cell growth in a dose dependent manner 24138843
U251  Function Assay 2/4/8 μℳ  6/12/24 h DMSO increases the LC3-II level in a time-dependent and dose-dependent manner 23799852
U87MG Function Assay 2/4/8 μℳ  6/12/24 h DMSO increases the LC3-II level in a time-dependent and dose-dependent manner 23799852
U251  Function Assay 4 μℳ  2/6/12 h DMSO suppresses basal levels of phosphorylation of S6 (S235/236), 4E-BP1 (T37/46), and Akt (S473) in a time-dependent manner  23799852
U87MG Function Assay 4 μℳ  2/6/12 h DMSO suppresses basal levels of phosphorylation of S6 (S235/236), 4E-BP1 (T37/46), and Akt (S473) in a time-dependent manner  23799852
H1650  Growth Inhibition Assay IC50=3.5±1.2 μM 23274758
HUVECs  Growth Inhibition Assay 72 h IC50 = 7.1 μmol/L 22611027
KYN-2  Growth Inhibition Assay 72 h IC50 = 8.1 μmol/L 22611027
HuH-7  Growth Inhibition Assay 72 h IC50 = 9.4 μmol/L 22611027
HUVECs  Function Assay 1/5/10 μM 1 h significantly inhibits VEGFR-2 phosphorylation 22611027
HAK1-B Function Assay 1/5/10 μM 1 h suppresses EGFR phosphorylation 22611027
UM-22A Growth Inhibition Assay 0-6 μM 72 h DMSO inhibits cell growth in a dose dependent manner 22307735
UM-22B Growth Inhibition Assay 0-6 μM 72 h DMSO inhibits cell growth in a dose dependent manner 22307735
PCI-37A Growth Inhibition Assay 0-6 μM 72 h DMSO inhibits cell growth in a dose dependent manner 22307735
PCI-37B Growth Inhibition Assay 0-6 μM 72 h DMSO inhibits cell growth in a dose dependent manner 22307735
PCI-15B Growth Inhibition Assay 0-6 μM 72 h DMSO inhibits cell growth in a dose dependent manner 22307735
SCC-25 Growth Inhibition Assay 0-6 μM 72 h DMSO inhibits cell growth in a dose dependent manner 22307735
UM-22A Function Assay 0-10 μM 24 h DMSO inhibits the activation of the EGFR tyrosine kinase and also decreases the expression of phosphorylated forms of the downstream signaling elements, STAT3 and MAPK 22307735
UM-22B Function Assay 0-10 μM 24 h DMSO inhibits the activation of the EGFR tyrosine kinase and also decreases the expression of phosphorylated forms of the downstream signaling elements, STAT3 and MAPK 22307735
PCI-15B Function Assay 0-10 μM 24 h DMSO inhibits the activation of the EGFR tyrosine kinase and also decreases the expression of phosphorylated forms of the downstream signaling elements, STAT3 and MAPK 22307735
PCI-37A Function Assay 1 μM 24 h DMSO downregulates VEGF production 22307735
UM-22A Function Assay 1 μM 24 h DMSO downregulates VEGF production 22307735
PCI-15B Function Assay 1 μM 24 h DMSO downregulates VEGF production 22307735
PCI-15B Invasion Assay 24 h DMSO EC50=558 nM 22307735
PCI-37A Invasion Assay 24 h DMSO EC50=1695 nM 22307735
UM-22A Invasion Assay 24 h DMSO EC50=0.3 nM 22307735
SCC-25 Invasion Assay 24 h DMSO EC50=10 nM 22307735
UM-22B Invasion Assay 24 h DMSO EC50=2424 nM 22307735
PCI-37B Invasion Assay 24 h DMSO EC50=1726 nM 22307735
201T Function Assay 2.5 μM 48 h DMSO inhibits phospho-MAPK following EGF 22258476
273T  Function Assay 2.5 μM 48 h DMSO inhibits phospho-MAPK following EGF 22258476
A549 Function Assay 2.5 μM 48 h DMSO inhibits phospho-MAPK following EGF 22258476
201T  Function Assay 1/5/10 μM 48 h DMSO blocks the phosphorylation of Akt induced by VEGFC 22258476
H2052 Growth Inhibition Assay IC50=1.07±0.04 μM 21970874
H2452 Growth Inhibition Assay IC50=3.52±1.13 μM 21970874
H28 Growth Inhibition Assay IC50=0.32±0.07 μM 21970874
MSTO-211H Growth Inhibition Assay IC50=1.42±0.03 μM 21970874
Hth83 Growth Inhibition Assay 72 h DMSO IC50=3.30 ± 0.66 μM 21220477
C643 Growth Inhibition Assay 72 h DMSO IC50=3.65 ± 1.22 μM 21220477
8505C Growth Inhibition Assay 72 h DMSO IC50=7.56 ± 1.13 μM 21220477
Hth74 Growth Inhibition Assay 72 h DMSO IC50=8.56 ± 1.01 μM 21220477
SW1736 Growth Inhibition Assay 72 h DMSO IC50=9.05 ± 0.55 μM 21220477
Hth7 Growth Inhibition Assay 72 h DMSO IC50=9.66 ± 0.38 μM 21220477
Hth104 Growth Inhibition Assay 72 h DMSO IC50=±16.98 ± NA μM 21220477
HTB3 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
HT1376 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
RT4 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
J82 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
CRL1749 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
T24 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
SUP Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
HTB9 Growth Inhibition Assay 0-20 μM 24 h inhibits cell growth in a dose dependent manner 19220256
ACC3 Growth Inhibition Assay 0-10 μM 72 h inhibits cell growth in a dose dependent manner 18698025
ACC2 Growth Inhibition Assay 0-10 μM 72 h inhibits cell growth in a dose dependent manner 18698025
ACCM Growth Inhibition Assay 0-10 μM 72 h inhibits cell growth in a dose dependent manner 18698025
ACC3 Apoptosisi Assay 0-10 μM 72 h induces apoptosis dose dependently 18698025
ACC2 Apoptosisi Assay 0-10 μM 72 h induces apoptosis dose dependently 18698025
ACCM Apoptosisi Assay 0-10 μM 72 h induces apoptosis dose dependently 18698025
EHMES-1 Growth Inhibition Assay 72 h DMSO IC50=10.6 μM 18364248
EHMES-10 Growth Inhibition Assay 72 h DMSO IC50=0.3 μM 18364248
211H Growth Inhibition Assay 72 h DMSO IC50=2.2 μM 18364248
H28 Growth Inhibition Assay 72 h DMSO IC50=1.8 μM 18364248
H2052 Growth Inhibition Assay 72 h DMSO IC50=8.0 μM 18364248
H2452 Growth Inhibition Assay 72 h DMSO IC50=5.5 μM 18364248
CNE-1 Growth Inhibition Assay 0.1-25.6 μM 48 h IC50=3.6 μM 17631646
CNE-2 Growth Inhibition Assay 0.1-25.6 μM 48 h IC50=6.2 μM 17631646
C666-1 Growth Inhibition Assay 0.1-25.6 μM 48 h IC50=23.4 μM 17631646
CNE-1 Growth Inhibition Assay 0.1-25.6 μM 72 h IC50=2.3 μM 17631646
CNE-2 Growth Inhibition Assay 0.1-25.6 μM 72 h IC50=3.6 μM 17631646
C666-1 Growth Inhibition Assay 0.1-25.6 μM 72 h IC50=4.86 μM 17631646
CNE-1 Function Assay 6 μM 24 h delays G0/G1 cell cycle progression 17631646
CNE-2 Function Assay 6 μM 24 h delays G0/G1 cell cycle progression 17631646
C666-1 Function Assay 6 μM 24 h delays G0/G1 cell cycle progression 17631646
KDR15 Function assay Inhibitory activity against VEGF stimulated autophosphorylation of VEGFR2 expressed in KDR15 cells, IC50 = 0.015 μM. 16302797
Sf9 Function assay Inhibition of human recombinant histidine-tagged RET (700-1020) expressed in Sf9 cells by ELISA, IC50 = 0.097 μM. 20409618
TPC1 Antiproliferative assay 72 hrs Antiproliferative activity against human TPC1 cells expressing RET/PCT1 after 72 hrs by [3H]thymidine incorporation assay, IC50 = 0.116 μM. 20409618
HEK293 Function assay Inhibition of FGFR1/VEGFR2 chimeric construct expressed in HEK293 cells by ELISA, ED50 = 0.15 μM. 19101155
Sf21 Function assay 15 mins Inhibition of recombinant His-tagged human KDR expressed in insect Sf21 cells preincubated for 15 mins followed by substrate addition measured after 20 mins by HTRF assay, IC50 = 0.175 μM. 26874741
umbilical vein endothelial cells Function assay Inhibition of VEGF-induced proliferation of human umbilical vein endothelial cells, IC50 = 0.4 μM. 15743202
BA/F3 Function assay 48 hrs Inhibition of KIF5B/RET (unknown origin) expressed in mouse BA/F3 cells assessed as reduction in cell viability after 48 hrs by Cell titre glo-based luminescence assay, IC50 = 0.4 μM. 26874741
BA/F3 Function assay 48 hrs Inhibition of KDR (unknown origin) expressed in mouse BA/F3 cells assessed as reduction in cell viability after 48 hrs by Cell titre glo-based luminescence assay, IC50 = 0.63 μM. 26874741
umbilical vein endothelial cells Function assay Inhibition of basic FGF-induced proliferation of human umbilical vein endothelial cells, IC50 = 1.2 μM. 15743202
HL60 Antiproliferative assay 72 hrs Antiproliferative activity against human HL60 cells after 72 hrs by MTT assay, IC50 = 1.492 μM. 26995527
293 Function assay Inhibitory activity against VEGFR2 transiently transfected in 293 adenovirus transfected kidney cells by ELISA, IC50 = 1.66 μM. 16275072
293 Function assay Inhibition of VEGFR2 in 293 adenovirus transfected kidney cells by cell-based ELISA assay, IC50 = 1.66 μM. 16321531
HEK293 Function assay Inhibition of VEGFR2 phosphorylation in HEK293 cells by cell-based ELISA, IC50 = 1.66 μM. 16460936
HT-29 Antiproliferative assay 72 hrs Antiproliferative activity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 1.925 μM. 26995527
DU145 Antiproliferative assay 72 hrs Antiproliferative activity against human DU145 cells after 72 hrs by MTT assay, IC50 = 1.974 μM. 26995527
MGHU3 Antiproliferative assay 72 hrs Antiproliferative activity against human MGHU3 cells after 72 hrs by CellTiter-Glo assay, IC50 = 2.5 μM. 30309671
A549 Antiproliferative assay 72 hrs Antiproliferative activity against human A549 cells after 72 hrs by CellTiter-Glo assay, IC50 = 2.5 μM. 30309671
RT112 Antiproliferative assay 72 hrs Antiproliferative activity against human RT112 cells after 72 hrs by CellTiter-Glo assay, IC50 = 2.5 μM. 30309671
A549 Antiproliferative assay 72 hrs Antiproliferative activity against human A549 cells after 72 hrs by MTT assay, IC50 = 2.63 μM. 26995527
CHO Function assay Inhibition of VEGFR induced autophosphorylation of human Vascular endothelial growth factor receptor 2 (VEGFR2) transfected in CHO cells, IC50 = 2.673 μM. 12477352
MCF7 Antiproliferative assay 72 hrs Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 3.536 μM. 26995527
PANC1 Antiproliferative assay 72 hrs Antiproliferative activity against human PANC1 cells after 72 hrs by MTT assay, IC50 = 4.107 μM. 26995527
HT-29 Antiproliferative assay 10 uM 72 hrs Antiproliferative activity against human HT-29 cells at 10 uM after 72 hrs by MTS assay, IC50 = 4.2 μM. 21353546
EAhy926 Antiproliferative assay 10 uM 72 hrs Antiproliferative activity against human EAhy926 cells at 10 uM after 72 hrs by MTS assay, IC50 = 5.1 μM. 21353546
MCF7 Antiproliferative assay 48 hrs Antiproliferative activity against human MCF7 cells measured after 48 hrs by MTT assay, IC50 = 11.83 μM. 27688180
MCF7 Cytotoxicity assay 48 hrs Cytotoxicity in human MCF7 cells assessed as inhibition of cell growth incubated for 48 hrs by MTT assay, IC50 = 16.52 μM. 28942113
MCF7 Antiproliferative assay 48 hrs Antiproliferative activity against human MCF7 cells after 48 hrs by MTT assay, IC50 = 18.5 μM. 26741358
MCF7 Antiproliferative assay 48 hrs Antiproliferative activity against human MCF7 cells after 48 hrs by MTT assay, IC50 = 18.5 μM. 26475519
HT-29 Antiproliferative assay 48 hrs Antiproliferative activity against human HT-29 cells measured after 48 hrs by MTT assay, IC50 = 18.95 μM. 27688180
H460 Antiproliferative assay 48 hrs Antiproliferative activity against human H460 cells measured after 48 hrs by MTT assay, IC50 = 37.1 μM. 27688180
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD 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
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells 29435139
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
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells 29435139
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Chemische Informationen, Lagerung & Stabilität (Chemical Information, Storage & Stability)

Molekulargewicht 475.35 Formel

C22H24BrFN4O2

 Lagerung (Ab dem Eingangsdatum)
CAS-Nr. 443913-73-3 SDF herunterladen Lagerung von Stammlösungen

Synonyme ZD6474 Smiles CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC

Löslichkeit (Solubility)

In vitro
Charge:

DMSO : 60 mg/mL (126.22 mM) Mit 60°C Wasserbad erwärmt; Ultraschallbehandelt;
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molaritätsrechner

Masse Konzentration Volumen Molekulargewicht
Verdünnungsrechner Molekulargewichtsrechner

In vivo
Charge:

In-vivo-Formulierungsrechner (Klare Lösung)

Schritt 1: Geben Sie die untenstehenden Informationen ein (Empfohlen: Ein zusätzliches Tier zur Berücksichtigung von Verlusten während des Experiments)

mg/kg g μL

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% DMSO % % Tween 80 % ddH2O
%DMSO %

Berechnungsergebnisse:

Arbeitskonzentration: mg/ml;

Methode zur Herstellung der DMSO-Stammlösung: mg Wirkstoff vorgelöst in μL DMSO ( Konzentration der Stammlösung mg/mL, Bitte kontaktieren Sie uns zuerst, wenn die Konzentration die DMSO-Löslichkeit der Wirkstoffcharge überschreitet. )

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammlösung, dann hinzufügenμL PEG300, mischen und klären, dann hinzufügenμL Tween 80, mischen und klären, dann hinzufügen μL ddH2O, mischen und klären.

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammlösung, dann hinzufügen μL Maisöl, mischen und klären.

Hinweis: 1. Bitte stellen Sie sicher, dass die Flüssigkeit klar ist, bevor Sie das nächste Lösungsmittel hinzufügen.
2. Achten Sie darauf, das/die Lösungsmittel der Reihe nach hinzuzufügen. Sie müssen sicherstellen, dass die bei der vorherigen Zugabe erhaltene Lösung eine klare Lösung ist, bevor Sie mit der Zugabe des nächsten Lösungsmittels fortfahren. Physikalische Methoden wie Vortex, Ultraschall oder ein heißes Wasserbad können zur Unterstützung des Lösens verwendet werden.

Wirkmechanismus (Mechanism of Action)

Targets/IC50/Ki
VEGFR2
(Cell-free assay)
40 nM
VEGFR3
(Cell-free assay)
110 nM
EGFR
(Cell-free assay)
500 nM
In vitro
Vandetanib also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. This compound is not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM, while almost has no activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM. It inhibits VEGF-, EGF- and bFGF-stimulated HUVEC proliferation with IC50 of 60 nM, 170 nM and 800 nM, with no effect on basal endothelial cell growth. This chemical inhibits tumor cell growth with IC50 of 2.7 μM (A549) to 13.5 μM (Calu-6). It displays an inhibitory effect on the basal ABCG2-ATPase. Parental and ABCG2-expressing A431 cells showed similar sensitivities toward this compound. Exposure to EGFR inhibitors decreases pEGFR levels in A431 cells, with this compound displaying only a moderate effect. It displays a slight but measurable effect, whereas gefitinib, pelitinib and neratinib completely inhibit ABCG2-mediated efflux of mitoxantrone from A431/ABCG2 cells, similarly to the specific ABCG2 inhibitor Ko143. It inhibits both PC3wt and PC3R cell lines with similar IC50 of 13.3 μM and 11.5 μM, respectively. This chemical suppresses phosphorylation of VEGFR2 in HUVEC and EGFR in hepatoma cells and inhibits cell proliferation. It causes an accumulation of cells in the G0-G1 phases in GEO and OVCAR-3 cells and increases apoptosis in OVCAR-3, ZR-75-1, MCF-10A ras, and GEO cells. This compound causes a dose-dependent inhibition of EGFR phosphorylation in mouse NIH-EGFR fibroblasts and human MCF-10A ras breast cancer cells, two cell lines that overexpress the human EGFR. It treatment results in a dose-dependent inhibition of soft agar growth in seven human cell lines (breast, colon, gastric, and ovarian) with functional EGFR but lacking VEGFR2.
Kinase-Assay
Kinase-Hemmung
Vandetanib wird mit dem Enzym, 10 mM MnCl2 und 2 μM ATP in 96-Well-Platten inkubiert, die mit einem Poly(Glu, Ala, Tyr) 6:3:1 Zufallscopolymer-Substrat beschichtet sind. Phosphoryliertes Tyrosin wird dann durch sequentielle Inkubation mit einem Maus-IgG-Anti-Phosphotyrosin-4G10-Antikörper, einem Meerrettichperoxidase-verknüpften Schaf-Anti-Maus-Immunglobulin-Antikörper und 2,2′-Azino-bis(3-ethylbenzthiazolin-6-sulfonsäure) nachgewiesen. Diese Methodik wird angepasst, um die Selektivität gegenüber Tyrosinkinasen, die mit EGFR, PDGFRβ, Tie-2, FGFR1, c-kit, erbB2, IGF-1R und FAK assoziiert sind, zu untersuchen. Alle Enzymassays (Tyrosin oder Serin-Threonin) verwendeten geeignete ATP-Konzentrationen bei oder knapp unter dem jeweiligen Km (0,2–14 μM). Die Selektivität gegenüber Serin-Threonin-Kinasen (CDK2, AKT und PDK1) wird unter Verwendung eines relevanten Szintillationsnäherungs-Assays (SPA) in 96-Well-Platten untersucht. CDK2-Assays enthielten 10 mM MnCl2, 4,5 μM ATP, 0,15 μCi [γ-33 P]ATP/Reaktion, 50 mM HEPES (pH 7,5), 1 mM DTT, 0,1 mM Natriumorthovanadat, 0,1 mM Natriumfluorid, 10 mM Natriumglycerophosphat, 1 mg/mL BSA-Fraktion V und ein Retinoblastom-Substrat (Teil des Retinoblastom-Gens, 792–928, exprimiert in einem Glutathion-S-Transferase-Expressionssystem; 0,22 μM Endkonzentration). Die Reaktionen werden 60 Minuten bei Raumtemperatur durchgeführt, bevor sie 2 Stunden lang mit 150 μL einer Lösung, die EDTA (62 mM Endkonzentration), 3 μg eines Kaninchen-Immunglobulin-Anti-Glutathion-S-Transferase-Antikörpers und Protein-A-SPA-Polyvinyltoluol-Beads (0,8 mg/Reaktion) enthält, gequencht werden. Die Platten werden dann versiegelt, zentrifugiert (1200 × g für 5 Minuten) und 30 Sekunden lang auf einem Mikrotiterplatten-Szintillationszähler gezählt.
In vivo
Vandetanib (2.5 mg/kg, i.v.), reverses a VEGF-induced hypotension by 63% but does not significantly affect a bFGF-induced hypotension. This compound (100 mg/kg) inhibits the tumor-induced blood vessel formation by 79%. It (12.5-100 mg/kg, orally) shows great tumor growth inhibition in human tumor xenografts including Calu-6, PC-3, MDA-MA-231, SKOV-3, SW620, A549, A431, B16-F10(AP3) and Lewis Lung, with little effects on body weight. In PC3wt xenografts, administration of this compound alone exerts paradoxical tumor growth stimulating effects. In PC3R xenografts, the low dose of this chemical (25 mg/kg) has no significant effect relative to control, whereas the high dose (50 mg/kg) significantly inhibits tumor growth compared with control. In contrast, the high-dose combination reveals a significant negative interaction between this compound 50 mg/kg and docetaxel 30 mg/kg in PC3R cells. In tumor-bearing mice, it suppresses phosphorylation of VEGFR2 and EGFR in tumor tissues, significantly decreases tumor vessel density, enhances tumor cell apoptosis, suppresses tumor growth, improves survival, reduces number of intrahepatic metastases, and up-regulates VEGF, TGF-alpha and EGF in tumor tissues. Treatment with this compound is not associated with serious adverse events, including ALT abnormality, bone marrow suppression or body weight loss. This chemical treatment of nude mice bearing palpable GEO colon cancer xenografts (which are sensitive to inhibition of EGFR signaling) induces dose-dependent tumor growth inhibition.
Literatur
  • [4] https://pubmed.ncbi.nlm.nih.gov/22611027/
  • [5] https://pubmed.ncbi.nlm.nih.gov/12684431/

Anwendungen (Applications)

Methoden Biomarker Bilder PMID
Western blot p-ERK / ERK / p-AKT / AKT p-EGFR / EGFR
S1046-WB1
19622715
Growth inhibition assay Cell viability
S1046-viability1
24261856

Klinische Studieninformationen (Clinical Trial Information)

(Daten von https://clinicaltrials.gov, aktualisiert am 2024-05-22)

NCT-Nummer Rekrutierung Erkrankungen Sponsor/Kooperationspartner Startdatum Phasen
NCT03291379 Completed
Carcinoma Hepatocellular|Metastatic Colorectal Cancer
Boston Scientific Corporation|Biocompatibles UK Ltd
 May 17 2017 Early Phase 1
NCT02495103 Terminated
Renal Cell Carcinoma|Hereditary Leiomyomatosis|Renal Cell Cancer
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)
 August 26 2015 Phase 1|Phase 2
NCT02530411 Unknown status
Neoplasms
Velindre NHS Trust|Cancer Research UK|AstraZeneca
 April 2015 Phase 2
NCT02268734 Completed
Metastatic Sporadic Medullary Thyroid Cancer
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
 April 2014 --
NCT01876784 Completed
Differentiated Thyroid Cancer
Genzyme a Sanofi Company|Sanofi
 September 17 2013 Phase 3
NCT01661179 Completed
Unresectable Locally Advanced or Metastatic Medullary Thyroid Carcinoma
Genzyme a Sanofi Company|Sanofi
 November 2012 Phase 1|Phase 2