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Dovitinib (TKI-258) FLT3 remmer

Name: Dovitinib (TKI-258)
Brand: Selleck Chemicals
SKU: S1018
Rating: 5 (53 reviews)

Cat.nr.S1018

Dovitinib (TKI-258, CHIR258) is een multitarget RTK-remmer, voornamelijk gericht op klasse III RTK's (FLT3/c-Kit) met IC50-waarden van 1 nM/2 nM. Het is ook potent tegen klasse IV (FGFR1/3) en klasse V (VEGFR1-4) RTK's, met IC50-waarden van 8–13 nM, terwijl het in celvrije assays een lagere potentie vertoont ten opzichte van InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R en HER2. Fase 4.

Dovitinib (TKI-258) FLT3 remmer Chemical Structure

Chemische structuur

Molecuulgewicht: 392.43

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Kwaliteitscontrole

Batch: Zuiverheid: 99.98%

99.98

Gerelateerde doelwitten	EGFR VEGFR JAK PDGFR FGFR Src HIF FLT HER2 Bcr-Abl
Overig FLT3 Inhibitoren	UNC2025 Crenolanib (CP-868596) Dovitinib (TKI258) Lactate monohydrate Tandutinib (MLN518) KW-2449 ENMD-2076 AST-487 (NVP-AST487) TCS 359 G-749 AMG 925

Celkweek, behandeling & werkzame concentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Formulering	Activiteitsbeschrijving	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
Klik om meer experimentele gegevens over cellijnen te bekijken

Chemische informatie, opslag en stabiliteit

Molecuulgewicht	392.43	Formule	C₂₁H₂₁FN₆O	Opslag (vanaf de datum van ontvangst)	3 jaar-20°Cpoeder
CAS-nr.	405169-16-6	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	CHIR-258			Smiles	CN1CCN(CC1)C2=CC3=C(C=C2)N=C(N3)C4=C(C5=C(C=CC=C5F)NC4=O)N

Oplosbaarheid

In vitro
Batch:

DMSO : 30 mg/mL (76.44 mM)
(Met vocht verontreinigd DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Molecuulgewicht
=	×	×

Verdunningscalculator Molecuulgewichtcalculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	30%PEG400 1 0.5%Tween80 2 5%propylene glycol Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	30.000mg/ml (76.45mM)	Taking the 1 mL working solution as an example, add 300 μL of 100 mg/ml clarified PEG400 stock solution to 5 μL of Tween80, mix evenly to clarify it; add 50 μL Propylene glycol to the above system, mix evenly to clarify it; then continue to add 645 μL ddH2O to adjust the volume. to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo formulatiecalculator (heldere oplossing)

Stap 1: Voer onderstaande informatie in (Aanbevolen: een extra dier om rekening te houden met verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in de sectie oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-moedervloeistof: mg geneesmiddel vooropgelost in μL DMSO ( Concentratie moedervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de batch van het geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toeμL PEG300, mengen en verhelderen, daarna toevoegenμL Tween 80, mengen en verhelderen, daarna toevoegen μL ddH₂O, mengen en verhelderen.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toe μL Maïsolie, mengen en verhelderen.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysieke methoden zoals vortexen, ultrasoon of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

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) remt krachtig de FGF-gestimuleerde groei van WT- en F384L-FGFR3-expresserende B9-cellen met een IC50 van 25 nM. Bovendien remt het de proliferatie van B9-cellen die elk van de verschillende geactiveerde mutanten van FGFR3 tot expressie brengen. Interessant is dat er minimale verschillen worden waargenomen in de gevoeligheid van de verschillende FGFR3-mutaties voor deze verbinding, waarbij de IC50 varieert van 70 tot 90 nM voor elk van de verschillende mutaties. IL-6-afhankelijke B9-cellen die alleen vector bevatten (B9-MINV-cellen) zijn resistent tegen de remmende activiteit bij concentraties tot 1 µM. Het remt de celproliferatie van KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E) en KMS18 (FGFR3-G384D) cellen met een IC50 van respectievelijk 90 nM (KMS11 en OPM2) en 550 nM. De verbinding remt FGF-gemedieerde ERK1/2-fosforylatie en induceert cytotoxiciteit in FGFR3-expresserende primaire MM-cellen. BMSCs verlenen een bescheiden mate van resistentie met 44,6% groeiremming voor cellen behandeld met 500 nM Dovitinib en gekweekt op stroma, vergeleken met 71,6% groeiremming voor cellen gekweekt zonder BMSCs. Het remt de proliferatie van M-NFS-60, een M-CSF-groeigedreven myeloblastische muizencellijn met een mediane effectieve concentratie (EC50) van 220 nM. Behandeling van SK-HEP1-cellen met deze verbinding resulteert in een dosisafhankelijke reductie in celgetal en G2/M-fasearrest met reductie in de G0/G1- en S-fasen, remming van verankeringonafhankelijke groei en blokkade van bFGF-geïnduceerde celmotiliteit. De IC50 hiervoor in SK-HEP1-cellen is ongeveer 1,7 µM. Het vermindert ook significant de basale fosforyleringsniveaus van FGFR-1, FGFR-substraat 2α (FRS2-α) en ERK1/2, maar niet Akt, in zowel SK-HEP1- als 21-0208-cellen. In 21-0208 HCC-cellen remt het significant de bFGF-geïnduceerde fosforylering van FGFR-1, FRS2-α, ERK1/2, maar niet Akt.
Kinase Assay	In vitro kinase assays
Kinase Assay	De remmende concentratie van 50% (IC50) waarden voor de remming van RTK's door Dovitinib (TKI-258) worden bepaald in een tijdopgeloste fluorescentie (TRF) of radioactief formaat, waarbij de remming van de fosfaatoordracht naar een substraat door het respectievelijke enzym wordt gemeten. De kinase-domeinen van FGFR3, FGFR1, PDGFRβ en VEGFR1-3 worden getest in 50 mM HEPES (N-2-hydroxyethylpiperazine-N′-2-ethaansulfonzuur), pH 7.0, 2 mM MgCl₂, 10 mM MnCl₂, 1 mM NaF, 1 mM dithiothreitol (DTT), 1 mg/mL bovine serumalbumine (BSA), 0,25 μM gebiotinyleerd peptidesubstraat (GGGGQDGKDYIVLPI) en 1 tot 30 μM adenosine trifosfaat (ATP) afhankelijk van de K_m voor het respectievelijke enzym. ATP-concentraties liggen op of net onder de K_m. Voor c-KIT- en FLT3-reacties wordt de pH verhoogd tot 7.5 met 0,2 tot 8 μM ATP in aanwezigheid van 0,25 tot 1 μM gebiotinyleerd peptidesubstraat (GGLFDDPSYVNVQNL). Reacties worden 1 tot 4 uur bij kamertemperatuur geïncubeerd en het gefosforyleerde peptide wordt op streptavidine-gecoate microtiterplaten met stopreactiebuffer (25 mM EDTA [ethyleendiaminetetraazijnzuur], 50 mM HEPES, pH 7.5) vastgelegd. Gefosforyleerd peptide wordt gemeten met het DELFIA TRF-systeem met behulp van een europium-gelabeld antifosfotyrosine-antilichaam PT66. De concentratie van deze verbinding voor IC50 wordt berekend met behulp van niet-lineaire regressie met XL-Fit data-analyse software versie 4.1 (IDBS). Remming van colony-stimulating factor-1 receptor (CSF-1R), PDGFRα, insulin receptor (InsR) en insulin-like growth factor receptor 1 (IGFR1) kinase-activiteit wordt bepaald bij ATP-concentraties dicht bij de K_m voor ATP.
In vivo	Dovitinib (TKI-258) induceert in vivo zowel cytostatische als cytotoxische reacties, resulterend in regressie van FGFR3-expresserende tumoren. Het vertoont een dosis- en blootstellingsafhankelijke remming van doelreceptortyrosinekinases (RTK's) die tot expressie komen in tumorxenografts. Deze verbinding remt krachtig de tumorgroei van zes HCC-lijnen. Remming van Angiogenesis correleerde met inactivatie van FGFR/PDGFRβ/VEGFR2-signaalroutes. In een orthotoop model remt het krachtig de primaire tumorgroei en longmetastase en verlengt het de overleving van muizen significant. Toediening van Dovitinib resulteert in significante tumorgroeiremming en tumorregressies, inclusief grote, gevestigde tumoren (500-1.000 mm³).
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/15598814/ [2] https://pubmed.ncbi.nlm.nih.gov/22027573/ [3] https://pubmed.ncbi.nlm.nih.gov/15897558/ [4] https://pubmed.ncbi.nlm.nih.gov/21521775/ [5] https://pubmed.ncbi.nlm.nih.gov/15598814/

Toepassingen

Methoden	Biomarkers	Afbeeldingen	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		24238094
Growth inhibition assay	Cell viability		28467797

Informatie over klinische proeven

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Werving	Aandoeningen	Sponsor/medewerkers	Startdatum	Fasen
NCT05571969	Recruiting	Advanced Solid Tumors	Allarity Therapeutics\|Amarex Clinical Research	February 20 2023	Phase 1
NCT02268435	Withdrawn	Gastrointestinal Stromal Tumors	Asan Medical Center	March 2015	Phase 1
NCT01700270	Completed	Advanced Solid Tumors Excluding Breast Cancer	Novartis Pharmaceuticals\|Novartis	May 2013	Phase 1
NCT01680796	Withdrawn	Multiple Myeloma	University of Florida\|Novartis Pharmaceuticals	February 2013	Phase 1
NCT01266070	Terminated	Von Hippel-Lindau Syndrome	M.D. Anderson Cancer Center\|Novartis	November 2012	Phase 2

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