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Dovitinib (TKI-258) FLT3 Inhibidor

Name: Dovitinib (TKI-258)
Brand: Selleck Chemicals
SKU: S1018
Rating: 5 (54 reviews)

Cat. No.S1018

Dovitinib (TKI-258, CHIR258) es un inhibidor de RTK multidirigido, que se dirige principalmente a los RTK de clase III (FLT3/c-Kit) con valores de IC50 de 1 nM/2 nM. También es potente contra los RTK de clase IV (FGFR1/3) y clase V (VEGFR1-4), exhibiendo valores de IC50 de 8-13 nM, mientras que muestra una menor potencia hacia InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R y HER2 en ensayos libres de células. Fase 4.

Dovitinib (TKI-258) FLT3 Inhibidor Chemical Structure

Estructura química

Peso molecular: 392.43

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Control de calidad (Quality Control)

Lote: Pureza: 99.98%

99.98

Dianas relacionadas	EGFR VEGFR JAK PDGFR FGFR Src HIF FLT HER2 Bcr-Abl
Otros FLT3 Inhibidores	UNC2025 Crenolanib (CP-868596) Dovitinib (TKI258) Lactate monohydrate Tandutinib (MLN518) ENMD-2076 KW-2449 AST-487 (NVP-AST487) TCS 359 G-749 FF-10101

Cultivo celular, tratamiento y concentración de trabajo
(Cell Culture, Treatment & Working Concentration)

Líneas celulares	Tipo de ensayo	Concentración	Tiempo de incubación	Formulación	Descripción de la actividad	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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Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular	392.43	Fórmula	C₂₁H₂₁FN₆O	Almacenamiento (Desde la fecha de recepción)	3 años-20°Cpolvo
Nº CAS	405169-16-6	Descargar SDF		Almacenamiento de soluciones madre	1 año-80°Cen disolvente 1 mes-20°Cen disolvente
Sinónimos	CHIR-258			Smiles	CN1CCN(CC1)C2=CC3=C(C=C2)N=C(N3)C4=C(C5=C(C=CC=C5F)NC4=O)N

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 30 mg/mL (76.44 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Water : Insoluble

Ethanol : Insoluble

Calculadora de Molaridad

Masa	Concentración	Volumen	Peso molecular
=	×	×

Calculadora de Dilución Calculadora de Peso Molecular

In vivo Lote:
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 Validado por los laboratorios Selleck. Si necesita ajustes en esta formulación, contacte con nuestro equipo de ventas para pruebas personalizadas.	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.

Calculadora de formulación in vivo (Solución clara)

Paso 1: Introduzca la información a continuación (Recomendado: Un animal adicional para tener en cuenta la pérdida durante el experimento)

Dosis: mg/kg Peso promedio de los animales: g Volumen de dosificación por animal:μL Número de animales:

Paso 2: Introduzca la formulación in vivo (Esto es solo la calculadora, no la formulación. Por favor, contáctenos primero si no hay una formulación in vivo en la sección de Solubilidad.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Resultados del cálculo:

Concentración de trabajo: mg/ml;

Método para preparar el líquido maestro de DMSO: mg fármaco predissuelto en μL DMSO ( Concentración del líquido maestro mg/mL, Por favor, contáctenos primero si la concentración excede la solubilidad del DMSO del lote del fármaco. )

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadirμL PEG300, mezclar y clarificar, luego añadirμL Tween 80, mezclar y clarificar, luego añadir μL ddH₂O, mezclar y clarificar.

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadir μL Aceite de maíz, mezclar y clarificar.

Nota: 1. Por favor, asegúrese de que el líquido esté claro antes de añadir el siguiente disolvente.
2. Asegúrese de añadir el (los) disolvente(s) en orden. Debe asegurarse de que la solución obtenida, en la adición anterior, sea una solución clara antes de proceder a añadir el siguiente disolvente. Se pueden utilizar métodos físicos como el vórtice, el ultrasonido o el baño de agua caliente para ayudar a la disolución.

Mecanismo de acción (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) inhibe potentemente el crecimiento estimulado por FGF de células B9 que expresan WT y F384L-FGFR3 con una IC50 de 25 nM. Además, inhibe la proliferación de células B9 que expresan cada una de las diversas mutantes activadas de FGFR3. Curiosamente, se observan diferencias mínimas en la sensibilidad de las diferentes mutaciones de FGFR3 a este compuesto, con la IC50 que oscila entre 70 y 90 nM para cada una de las diversas mutaciones. Las células B9 dependientes de IL-6 que contienen solo el vector (células B9-MINV) son resistentes a su actividad inhibidora en concentraciones de hasta 1 µM. Inhibe la proliferación celular de células KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E) y KMS18 (FGFR3-G384D) con una IC50 de 90 nM (KMS11 y OPM2) y 550 nM, respectivamente. El compuesto inhibe la fosforilación de ERK1/2 mediada por FGF e induce citotoxicidad en células primarias de MM que expresan FGFR3. Las BMSCs confieren un modesto grado de resistencia con una inhibición del crecimiento del 44,6 % para las células tratadas con 500 nM de Dovitinib y cultivadas en estroma en comparación con una inhibición del crecimiento del 71,6 % para las células cultivadas sin BMSCs. Inhibe la proliferación de M-NFS-60, una línea celular mieloblástica de ratón impulsada por el crecimiento de M-CSF con una concentración efectiva mediana (EC50) de 220 nM. El tratamiento de células SK-HEP1 con este compuesto resulta en una reducción dosis-dependiente del número de células y un arresto en fase G2/M con reducción en las fases G0/G1 y S, inhibición del crecimiento independiente del anclaje y bloqueo de la motilidad celular inducida por bFGF. La IC50 para este compuesto en células SK-HEP1 es aproximadamente de 1,7 µM. También reduce significativamente los niveles de fosforilación basal de FGFR-1, el sustrato 2α de FGFR (FRS2-α) y ERK1/2, pero no de Akt, tanto en células SK-HEP1 como en 21-0208. En células HCC 21-0208, inhibe significativamente la fosforilación inducida por bFGF de FGFR-1, FRS2-α, ERK1/2, pero no de Akt.
Ensayo de quinasa	Ensayos de quinasa in vitro
Ensayo de quinasa	Los valores de concentración inhibitoria al 50 % (IC50) para la inhibición de RTKs por Dovitinib (TKI-258) se determinan en un formato de fluorescencia resuelta en el tiempo (TRF) o radiactivo, midiendo su inhibición de la transferencia de fosfato a un sustrato por la enzima respectiva. Los dominios quinasa de FGFR3, FGFR1, PDGFRβ y VEGFR1-3 se ensayan en 50 mM HEPES (ácido N-2-hidroxietilpiperazina-N′-2-etanosulfónico), pH 7.0, 2 mM MgCl₂, 10 mM MnCl₂, 1 mM NaF, 1 mM ditiotreitol (DTT), 1 mg/mL de albúmina sérica bovina (BSA), 0,25 μM de péptido sustrato biotinilado (GGGGQDGKDYIVLPI) y 1 a 30 μM de adenosín trifosfato (ATP) dependiendo del K_m para la enzima respectiva. Las concentraciones de ATP están en o justo por debajo del K_m. Para las reacciones de c-KIT y FLT3, el pH se eleva a 7.5 con 0,2 a 8 μM de ATP en presencia de 0,25 a 1 μM de péptido sustrato biotinilado (GGLFDDPSYVNVQNL). Las reacciones se incuban a temperatura ambiente durante 1 a 4 horas y el péptido fosforilado se captura en placas de microtitulación recubiertas de estreptavidina que contienen tampón de detención de reacción (25 mM EDTA [ácido etilendiaminotetraacético], 50 mM HEPES, pH 7.5). El péptido fosforilado se mide con el sistema DELFIA TRF utilizando un anticuerpo antifosfotirosina PT66 marcado con europio. La concentración de este compuesto para IC50 se calcula utilizando regresión no lineal con el software de análisis de datos XL-Fit versión 4.1 (IDBS). La inhibición de la actividad quinasa del receptor del factor estimulante de colonias-1 (CSF-1R), PDGFRα, receptor de insulina (InsR) y receptor del factor de crecimiento similar a la insulina 1 (IGFR1) se determina a concentraciones de ATP cercanas al K_m para ATP.
In vivo	Dovitinib (TKI-258) induce respuestas tanto citostáticas como citotóxicas in vivo, lo que resulta en la regresión de tumores que expresan FGFR3. Muestra una inhibición dosis y exposición-dependiente de los receptores tirosina quinasas (RTKs) diana expresados en xenoinjertos tumorales. Este compuesto inhibe potentemente el crecimiento tumoral de seis líneas de HCC. La inhibición de la Angiogenesis se correlacionó con la inactivación de las vías de señalización FGFR/PDGFRβ/VEGFR2. En un modelo ortotópico, inhibe potentemente el crecimiento tumoral primario y la metástasis pulmonar y prolonga significativamente la supervivencia de los ratones. La administración de Dovitinib resulta en una inhibición significativa del crecimiento tumoral y regresiones tumorales, incluyendo tumores grandes y establecidos (500-1.000 mm³).
Referencias	[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/

Aplicaciones (Applications)

Métodos	Biomarcadores	Imágenes	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

Información del ensayo clínico (Clinical Trial Information)

(datos de https://clinicaltrials.gov, actualizado el 2024-05-22)

Número NCT	Reclutamiento	Condiciones	Patrocinador/Colaboradores	Fecha de inicio	Fases
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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