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Dovitinib (TKI-258) FLT3 Inhibitor

Kat.-Nr.: S1018

Dovitinib (TKI-258, CHIR258) ist ein Multitarget-RTK-Inhibitor, der primär auf Klasse III RTKs (FLT3/c-Kit) mit IC50-Werten von 1 nM/2 nM abzielt. Er ist auch wirksam gegen Klasse IV (FGFR1/3) und Klasse V (VEGFR1-4) RTKs mit IC50-Werten von 8–13 nM, während er in zellfreien Assays eine geringere Wirksamkeit gegenüber InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R und HER2 zeigt. Phase 4.
Dovitinib (TKI-258) FLT3 Inhibitor Chemical Structure

Chemische Struktur

Molekulargewicht: 392.43

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Qualitätskontrolle (Quality Control)

Charge: Reinheit: 99.98%
99.98

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

Zelllinien Assay-Typ Konzentration Inkubationszeit Formulierung Aktivitätsbeschreibung PMID
SupB15 Growth Inhibition Assay IC50=0.449 μM 25202073
SupB15-R Growth Inhibition Assay IC50=0.558 μM 25202073
BaF3-pSRα Growth Inhibition Assay IC50=0.668 μM 25202073
BaF3-p210Bcr-Abl Growth Inhibition Assay IC50=0.692 μM 25202073
BaF3-p210Bcr-Abl-T315I Growth Inhibition Assay IC50=2.626 μM 25202073
CCRF-CEM Growth Inhibition Assay IC50=0.398 μM 25202072
CEM/C2 Growth Inhibition Assay IC50=1.125 μM 25202072
Nalm-6 Growth Inhibition Assay IC50=0.382 μM 25202072
SEM-K2 Growth Inhibition Assay IC50=0.022 μM 25202072
HB-1119 Growth Inhibition Assay IC50=0.028 μM 25202072
RS4:11 Growth Inhibition Assay IC50=2.81 μM 25202072
Nalm-6 Apoptosis Assay 2 μM 24/48 h induces apoptosis resulting in about 72% of cell death after 24 h treatment and 81% after 48 h 25202072
SEM-K2 Apoptosis Assay 0.1/1 μM 24 h induces early apoptosis of SEM-K2 cells at 0.1 μM after 24 h 25202072
HCT-116 Growth Inhibition Assay IC50=3.050.58 μM 24495750
HT-29 Growth Inhibition Assay IC50=5.21.93 μM 24495750
SW-480 Growth Inhibition Assay IC50=4.330.47 μM 24495750
CaCO2 Growth Inhibition Assay IC50=3.230.64 μM 24495750
LS174T Growth Inhibition Assay IC50=4.330.47 μM 24495750
HEC-1A Function Assay 0.05/0.1/0.5 μM 72 h causes a decrease in STAT3, ERK, and AKT phosphorylation 24495750
AN3CA Function Assay 0.05/0.1/0.5 μM 72 h causes a decrease in STAT3, ERK, and AKT phosphorylation 24495750
MFE-296  Function Assay 0.05/0.1/0.5 μM 72 h causes a decrease in STAT3, ERK, and AKT phosphorylation 24495750
UMC3 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
5637 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
HU456 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
MGHU4 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
HT1376 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
RT112 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
T24 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
BFTC905 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
TCC-SUP Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
RT4 Cell Viability Assay 1-10 μM 72 h inhibits cell growth in a dose dependent manner 24325461
HONE1 Growth Inhibition Assay 0.1-10 μM 48 h induces G2/M delay in a concentration-dependent manner 24238094
HNE1 Growth Inhibition Assay 0.1-10 μM 48 h induces G2/M delay in a concentration-dependent manner 24238094
CNE2  Growth Inhibition Assay 0.1-10 μM 48 h induces G2/M delay in a concentration-dependent manner 24238094
C666-1 Growth Inhibition Assay 0.1-10 μM 48 h induces G2/M delay in a concentration-dependent manner 24238094
HeLa Growth Inhibition Assay 0.1-10 μM 24 h induces G2/M arrest in a concentration-dependent manner 24238094
Hep3B Growth Inhibition Assay 0.1-10 μM 24 h induces G2 arrest  24238094
HepG2 Growth Inhibition Assay 48 h IC50=2.727 ± 0.429 μM 23546591
Hep3B Growth Inhibition Assay 48 h IC50=4.223 ± 0.839 μM 23546591
PLC/PRF5 Growth Inhibition Assay 48 h IC50=16.120 ± 4.001 μM 23546591
Huh7 Growth Inhibition Assay 48 h IC50=15.007 ± 7.334 μM 23546591
HepG2 Growth Inhibition Assay 72 h IC50=1.200 ± 0.226 μM 23546591
Hep3B Growth Inhibition Assay 72 h IC50=0.892 ± 0.044 μM 23546591
PLC/PRF5 Growth Inhibition Assay 72 h IC50=3.110 ± 0.337 μM 23546591
Huh7 Growth Inhibition Assay 72 h IC50=3.980 ± 0.803 μM 23546591
MFE280 Growth Inhibition Assay IC50=0.42 ± 0.06 μM 23443805
AN3CA Growth Inhibition Assay IC50=0.50 ± 0.10 μM 23443805
HEC155 Growth Inhibition Assay IC50=0.66 ± 0.09 μM 23443805
MFE296 Growth Inhibition Assay IC50=0.66 ± 0.19 μM 23443805
SPAC1S Growth Inhibition Assay IC50=0.77 ± 0.08 μM 23443805
RL952 Growth Inhibition Assay IC50=0.93 ± 0.01 μM 23443805
EN1 Growth Inhibition Assay IC50=1.02 ± 0.25 μM 23443805
SNGII Growth Inhibition Assay IC50=1.24 ± 0.28 μM 23443805
ISHIKAWA Growth Inhibition Assay IC50=1.30 ± 0.11 μM 23443805
HEC1A Growth Inhibition Assay IC50=1.34 ± 0.30 μM 23443805
KLE Growth Inhibition Assay IC50=1.37 ± 0.02 μM 23443805
SNGM Growth Inhibition Assay IC50=1.42 ± 0.13 μM 23443805
USPC2 Growth Inhibition Assay IC50=1.62 ± 0.01 μM 23443805
EN Growth Inhibition Assay IC50=1.66 ± 0.01 μM 23443805
MFE319 Growth Inhibition Assay IC50=1.87 ± 0.45 μM 23443805
EFE184 Growth Inhibition Assay IC50=2.04 ± 0.13 μM 23443805
ECC1 Growth Inhibition Assay IC50=2.07 ± 0.01 μM 23443805
HEC1B Growth Inhibition Assay IC50=2.57 ± 0.23 μM 23443805
USPC1 Growth Inhibition Assay IC50=2.60 ± 0.13 μM 23443805
SPAC1L Growth Inhibition Assay IC50=3.06 ± 1.14 μM 23443805
HUVEC Cell Viability Assay 0-25 μM 72 h DMSO inhibits cell growth in a dose dependent manner 23228017
HMVEC Cell Viability Assay 0-25 μM 72 h DMSO inhibits cell growth in a dose dependent manner 23228017
MHCC-97H Cell Viability Assay 0-25 μM 72 h DMSO inhibits cell growth in a dose dependent manner 23228017
SMMC7721 Cell Viability Assay 0-25 μM 72 h DMSO inhibits cell growth in a dose dependent manner 23228017
Huh-7 Apoptosis Assay 0-12.5 μM 24 h DMSO  sensitizes HCC cells to TRAIL- and tigatuzumab-induced apoptosis in a dose-dependent manner 22230479
Sk-Hep1 Apoptosis Assay 0-12.5 μM 24 h DMSO  sensitizes HCC cells to TRAIL- and tigatuzumab-induced apoptosis in a dose-dependent manner 22230479
Hep3B Apoptosis Assay 0-12.5 μM 24 h DMSO  sensitizes HCC cells to TRAIL- and tigatuzumab-induced apoptosis in a dose-dependent manner 22230479
PLC5 Apoptosis Assay 0-12.5 μM 24 h DMSO  sensitizes HCC cells to TRAIL- and tigatuzumab-induced apoptosis in a dose-dependent manner 22230479
PLC5 Cell Viability Assay 0-15 μM 72 h reduces cell viability in a dose-dependent manner  22180308
Hep3B Cell Viability Assay 0-15 μM 72 h reduces cell viability in a dose-dependent manner  22180308
Sk-Hep1 Cell Viability Assay 0-15 μM 72 h reduces cell viability in a dose-dependent manner  22180308
Huh-7 Cell Viability Assay 0-15 μM 72 h reduces cell viability in a dose-dependent manner  22180308
PLC5 Apoptosis Assay 0-15 μM 24 h increases apoptotic cell death in a dose-dependent manner  22180308
Hep3B Apoptosis Assay 0-15 μM 24 h increases apoptotic cell death in a dose-dependent manner  22180308
Sk-Hep1 Apoptosis Assay 0-15 μM 24 h increases apoptotic cell death in a dose-dependent manner  22180308
Huh-7 Apoptosis Assay 0-15 μM 24 h increases apoptotic cell death in a dose-dependent manner  22180308
PLC5 Function Assay 0-10 μM 24 h causes dose-dependent DNA fragmentation 22180308
Hep3B Function Assay 0-10 μM 24 h causes dose-dependent DNA fragmentation 22180308
Sk-Hep1 Function Assay 0-10 μM 24 h causes dose-dependent DNA fragmentation 22180308
Huh-7 Function Assay 0-10 μM 24 h causes dose-dependent DNA fragmentation 22180308
SW780 Growth Inhibition Assay 5 d IC50=50 nM 21119661
RT112 Growth Inhibition Assay 5 d IC50=15 nM 21119661
RT4 Growth Inhibition Assay 5 d IC50=5 nM 21119661
JMSU1 Growth Inhibition Assay 5 d IC50=50 nM 21119661
J82 Growth Inhibition Assay 5 d IC50=1400 nM 21119661
97-7 Growth Inhibition Assay 5 d IC50=1000 nM 21119661
RT112 Function Assay 500 nM 24 h increases the proportion of cells in G1 accompanied by a decrease in S and G2/M phases 21119661
RT4 Function Assay 500 nM 24 h increases the proportion of cells in G1 accompanied by a decrease in S and G2/M phases 21119661
MGH-U3 Function Assay 500 nM 24 h increases the proportion of cells in G1 accompanied by a decrease in S and G2/M phases 21119661
SW780 Function Assay 500 nM 24 h increases the proportion of cells in G1 accompanied by a decrease in S and G2/M phases 21119661
97-7 Function Assay 500 nM 24 h increases the proportion of cells in G1 accompanied by a decrease in S and G2/M phases 21119661
 J807C Cell Viability Assay 0-400 nM 48 h inhibits cell growth in a dose dependent manner 15598814
Y373C Cell Viability Assay 0-400 nM 48 h inhibits cell growth in a dose dependent manner 15598814
K650E Cell Viability Assay 0-400 nM 48 h inhibits cell growth in a dose dependent manner 15598814
G384D Cell Viability Assay 0-400 nM 48 h inhibits cell growth in a dose dependent manner 15598814
F384L Cell Viability Assay 0-400 nM 48 h inhibits cell growth in a dose dependent manner 15598814
KMS11 Growth Inhibition Assay 72 h IC50=90 nM 15598814
KMS18 Growth Inhibition Assay 72 h IC50=550 nM 15598814
OPM2 Growth Inhibition Assay 72 h IC50=90 nM 15598814
H929 Growth Inhibition Assay 72 h IC50> 2500 nM 15598814
8226 Growth Inhibition Assay 72 h IC50> 2500 nM 15598814
U266 Growth Inhibition Assay 72 h IC50> 2500 nM 15598814
KM12L4A Function assay Inhibition of VEGFR2 phosphorylation expressed in human KM12L4A cells by Western blot analysis, EC50=0.046μM 19113866
KM12L4A Function assay Inhibition of PDGFRbeta phosphorylation expressed in human KM12L4A cells Western blot analysis, EC50=0.051μM 19113866
KM12L4A Function assay Inhibition of FGFR1 phosphorylation expressed in human KM12L4A cells by Western blot analysis, EC50=0.166μM 19113866
insect cells Function assay 1 to 4 hrs Inhibition of recombinant PDGFRbeta (unknown origin) expressed in baculovirus infected insect cells using biotinylated peptide substrate GGLFDDPSYVNVQNL in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescence assay, IC50=0.001μM 27914362
Sf9 Function assay 1 to 4 hrs Inhibition of recombinant human N-terminal GST/His6-tagged c-KIT (544 to 976 residues) expressed in baculovirus infected sf9 cells using biotinylated peptide substrate GGLFDDPSYVNVQNL in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescen, IC50=0.001μM 27914362
Sf9 Function assay 1 to 4 hrs Inhibition of recombinant human N-terminal GST/His6-tagged FLT3 (571 to 993 residues) expressed in baculovirus infected sf9 cells using biotinylated peptide substrate GGLFDDPSYVNVQNL in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescenc, IC50=0.001μM 27914362
insect cells Function assay 1 to 4 hrs Inhibition of recombinant FGFR1 (unknown origin) expressed in baculovirus infected insect cells using biotinylated peptide substrate GGGGQDGKDYIVLPI in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescence assay, IC50=0.008μM 27914362
insect cells Function assay 1 to 4 hrs Inhibition of recombinant VEGFR3 (unknown origin) expressed in baculovirus infected insect cells using biotinylated peptide substrate GGGGQDGKDYIVLPI in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescence assay, IC50=0.008μM 27914362
insect cells Function assay 1 to 4 hrs Inhibition of recombinant VEGFR1 (unknown origin) expressed in baculovirus infected insect cells using biotinylated peptide substrate GGGGQDGKDYIVLPI in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescence assay, IC50=0.01μM 27914362
insect cells Function assay 1 to 4 hrs Inhibition of recombinant VEGFR2 (unknown origin) expressed in baculovirus infected insect cells using biotinylated peptide substrate GGGGQDGKDYIVLPI in presence of ATP incubated for 1 to 4 hrs by time resolved fluorescence assay, IC50=0.013μM 27914362
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 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
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
U-2 OS qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 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
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 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
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 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
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
insect cells Function assay 1 to 4 hrs Inhibition of recombinant FGFR1 (unknown origin) expressed in baculovirus infected insect cells using GGGGQDGKDYIVLPI as substrate after 1 to 4 hrs by time-resolved fluorescence assay, IC50=0.008μM 30503938
NCI-H1703 Function assay 10 uM 24 hrs Inhibition of TNIK in human NCI-H1703 cells transfected with lentiviral vector 7TFP assessed as reduction of GSK3 inhibitor X activated TNIK-mediated Wnt/TCF/beta-catenin-dependent transcription at 10 uM after 24 hrs by luciferase reporter assay ChEMBL
LoVo Cytotoxicity assay 10 uM 72 hrs Cytotoxicity against Wnt/beta-catenin signalling dependent human LoVo cells assessed as cell viability at 10 uM after 72 hrs by ATPlite assay ChEMBL
HCT116 Cytotoxicity assay 10 uM 72 hrs Cytotoxicity against Wnt/beta-catenin signalling dependent human HCT116 cells assessed as cell viability at 10 uM after 72 hrs by ATPlite assay ChEMBL
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Chemische Informationen, Lagerung & Stabilität (Chemical Information, Storage & Stability)

Molekulargewicht 392.43 Formel

C21H21FN6O

 Lagerung (Ab Erhaltdatum)
CAS-Nr. 405169-16-6 SDF herunterladen Lagerung von Stammlösungen

Synonyme CHIR-258 Smiles CN1CCN(CC1)C2=CC3=C(C=C2)N=C(N3)C4=C(C5=C(C=CC=C5F)NC4=O)N

Löslichkeit (Solubility)

In vitro
Charge:

DMSO : 30 mg/mL (76.44 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molaritätsrechner

Masse Konzentration Volumen Molekulargewicht
Verdünnungsrechner Molekulargewicht-Rechner

In vivo
Charge:

In-vivo-Formulierungsrechner (Klare Lösung)

Schritt 1: Geben Sie unten die Informationen ein (Empfohlen: Ein zusätzliches Tier einplanen, um Verluste während des Experiments auszugleichen)

mg/kg g μL

Schritt 2: Geben Sie die In-vivo-Formulierung ein (Dies ist nur der Rechner, nicht die Formulierung. Bitte kontaktieren Sie uns zuerst, wenn im Abschnitt Löslichkeit keine In-vivo-Formulierung angegeben ist.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Berechnungsergebnisse:

Arbeitskonzentration: mg/ml;

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

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammflüssigkeit, fügen Sie als Nächstes hinzuμL PEG300, mischen und aufklären, fügen Sie als Nächstes hinzuμL Tween 80, mischen und aufklären, fügen Sie als Nächstes hinzu μL ddH2O, mischen und aufklären.

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammflüssigkeit, fügen Sie als Nächstes hinzu μL Maisöl, mischen und aufklären.

Hinweis: 1. Bitte stellen Sie sicher, dass die Flüssigkeit klar ist, bevor Sie das nächste Lösungsmittel hinzufügen.
2. Achten Sie darauf, die Lösungsmittel in der richtigen Reihenfolge hinzuzufügen. Sie müssen sicherstellen, dass die im vorherigen Schritt erhaltene Lösung klar ist, bevor Sie das nächste Lösungsmittel hinzufügen. Physikalische Methoden wie Vortexen, Ultraschall oder ein warmes Wasserbad können zur Unterstützung des Lösungsvorgangs verwendet werden.

Wirkungsmechanismus (Mechanism of Action)

Targets/IC50/Ki
FLT3
(Cell-free assay)
1 nM
c-Kit
(Cell-free assay)
2 nM
FGFR1
(Cell-free assay)
8 nM
VEGFR3/FLT4
(Cell-free assay)
8 nM
FGFR3
(Cell-free assay)
9 nM
VEGFR1/FLT1
(Cell-free assay)
10 nM
VEGFR2/Flk1
(Cell-free assay)
13 nM
PDGFRβ
(Cell-free assay)
27 nM
CSF-1R/c-Fms
(Cell-free assay)
36 nM
In vitro

Dovitinib (TKI-258) potently inhibits the FGF-stimulated growth of WT and F384L-FGFR3-expressing B9 cells with IC50 of 25 nM. In addition, it inhibits proliferation of B9 cells expressing each of the various activated mutants of FGFR3. Interestingly, there are minimal observed differences in the sensitivity of the different FGFR3 mutations to this compound, with the IC50 ranging from 70 to 90 nM for each of the various mutations. IL-6-dependent B9 cells containing vector only (B9-MINV cells are resistant to its inhibitory activity at concentrations up to 1 μM. It inhibits cell proliferation of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells with IC50 of 90 nM (KMS11 and OPM2) and 550 nM, respectively. The compound inhibits FGF-mediated ERK1/2 phosphorylation and induces cytotoxicity in FGFR3-expressing primary MM cells. BMSCs does confer a modest degree of resistance with 44.6% growth inhibition for cells treated with 500 nM Dovitinib and cultured on stroma compared with 71.6% growth inhibition for cells grown without BMSCs. It inhibits proliferation of M-NFS-60, an M-CSF growth-driven mouse myeloblastic cell line with a median effective concentration (EC50) of 220 nM. Treatment of SK-HEP1 cells with this compound results in a dose-dependent reduction in cell number and G2/M phase arrest with reduction in the G0/G1 and S phases, inhibition of anchorage-independent growth and blockage of bFGF-induced cell motility. The IC50 for it in SK-HEP1 cells is approximately 1.7 μM. It also significantly reduces the basal phosphorylation levels of FGFR-1, FGFR substrate 2α (FRS2-α) and ERK1/2 but not Akt in both SK-HEP1 and 21-0208 cells. In 21-0208 HCC cells, it significantly inhibits bFGF-induced phosphorylation of FGFR-1, FRS2-α, ERK1/2 but not Akt.

Kinase-Assay
In-vitro-Kinase-Assays
Die 50%igen Hemmkonzentrationen (IC50-Werte) für die Hemmung von RTKs durch Dovitinib (TKI-258) werden in einem zeitaufgelösten Fluoreszenz- (TRF) oder radioaktiven Format bestimmt, indem die Hemmung der Phosphatübertragung auf ein Substrat durch das jeweilige Enzym gemessen wird. Die Kinase-Domänen von FGFR3, FGFR1, PDGFRβ und VEGFR1-3 werden in 50 mM HEPES (N-2-Hydroxyethylpiperazin-N′-2-ethansulfonsäure), pH 7,0, 2 mM MgCl2, 10 mM MnCl2, 1 mM NaF, 1 mM Dithiothreitol (DTT), 1 mg/mL Rinderserumalbumin (BSA), 0,25 μM biotinyliertem Peptidsubstrat (GGGGQDGKDYIVLPI) und 1 bis 30 μM Adenosintriphosphat (ATP) in Abhängigkeit vom Km für das jeweilige Enzym untersucht. Die ATP-Konzentrationen liegen bei oder knapp unter Km. Für c-KIT- und FLT3-Reaktionen wird der pH-Wert auf 7,5 erhöht, mit 0,2 bis 8 μM ATP in Gegenwart von 0,25 bis 1 μM biotinyliertem Peptidsubstrat (GGLFDDPSYVNVQNL). Die Reaktionen werden bei Raumtemperatur 1 bis 4 Stunden inkubiert und das phosphorylierte Peptid auf Streptavidin-beschichteten Mikrotiterplatten, die Stoppreaktionspuffer (25 mM EDTA [Ethylendiamintetraessigsäure], 50 mM HEPES, pH 7,5) enthalten, eingefangen. Phosphoryliertes Peptid wird mit dem DELFIA TRF-System unter Verwendung eines Europium-markierten Anti-Phosphotyrosin-Antikörpers PT66 gemessen. Die Konzentration dieser Verbindung für IC50 wird mittels nichtlinearer Regression mit der XL-Fit-Datenanalysesoftware Version 4.1 (IDBS) berechnet. Die Hemmung der Kinaseaktivität des Kolonie-stimulierenden Faktor-1-Rezeptors (CSF-1R), PDGFRα, Insulinrezeptors (InsR) und Insulin-ähnlichen Wachstumsfaktorrezeptors 1 (IGFR1) wird bei ATP-Konzentrationen nahe dem Km für ATP bestimmt.
In vivo

Dovitinib (TKI-258) induces both cytostatic and cytotoxic responses in vivo resulting in regression of FGFR3-expressing tumors. It shows a dose- and exposure-dependent inhibition of target receptor tyrosine kinases (RTKs) expressed in tumor xenografts. This compound potently inhibits tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFRβ/VEGFR2 signaling pathways. In an orthotopic model, it potently inhibits primary tumor growth and lung metastasis and significantly prolonged mouse survival. Administration of Dovitinib results in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm3).

Referenzen
  • [4] https://pubmed.ncbi.nlm.nih.gov/21521775/
  • [5] https://pubmed.ncbi.nlm.nih.gov/15598814/

Anwendungen (Applications)

Methoden Biomarker Bilder PMID
Western blot CDK1 / p-CDK1 / p53 / p21 p-PDGFR-β / PDGFR-β / p-ERK / ERK p-VEGFR-2 / VEGFR-2 / p-FGFR-1 / FGFR-1 p-STAT3 / STAT3 / Mcl-1 / LC3 / Beclin 1 / p62
S1018-WB1
24238094
Growth inhibition assay Cell viability
S1018-viability1
28467797

Informationen zu klinischen Studien (Clinical Trial Information)

(Daten von https://clinicaltrials.gov, aktualisiert am 2026-06-01)

NCT-Nummer Rekrutierung Bedingungen Sponsor/Kollaboratoren Startdatum Phases
NCT05571969 TERMINATED
Advanced Solid Tumors
Allarity Therapeutics
 2023-03-08 PHASE1
NCT05571969 Recruiting
Advanced Solid Tumors
Allarity Therapeutics|Amarex Clinical Research
 2023-02-20 Phase 1
NCT00831792 COMPLETED
Prostate Cancer
M.D. Anderson Cancer Center
 2010-04-07 PHASE2
NCT01994590 TERMINATED
Prostate Cancer
M.D. Anderson Cancer Center
 2014-05-19 PHASE2
NCT01732107 TERMINATED
Bladder Cancer
Noah Hahn, M.D.
 2013-03 PHASE2
NCT02116803 COMPLETED
Solid Tumors
Novartis Pharmaceuticals
 2014-05-28 PHASE2; PHASE3