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Nintedanib

Nintedanib

Item no.	S1010-5000
Manufacturer	Selleckchem
CASRN	656247-17-5
Amount	5 g
Quantity options	10 mg 1 g 10 g 10 mM/1 mL 200 mg 5 mg 50 mg 5 g
Category	Oncology Food Safety Drugs Neuroscience Neural Signaling Inhibitors & Compound Libraries Small Molecules By Organ Skin Cancer Colorectal Cancer Uterine, Ovarian & Cervical Cancer
Type	Inhibitors
Specific against	other
Smiles	CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N=C(C3=CC=CC=C3)C4=C(NC5=C4C=CC(=C5)C(=O)OC)O
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	BIBF 1120,Intedanib
Similar products	BIBF1120
Available
Storage Conditions	2 years -80 in solvent
Molecular Weight	539, 62
Administration	p.o.
Animal Models	FaDu, Caki-1, SKOV-3, H460, HT-29, or PAC-120 xenografts in Athymic NMRI-nu/nu female mice
Cell lines	HUVEC, HUASMC, and BRP cell lines
Clinical Trials	BIBF1120 is currently in a Phase III clinical trial in treatment of ovarian neoplasms.
Concentrations	50 nM
Dosages	100 mg/kg
Formulation	In a 0.5 % Natrosol solution
IC50	34 nM/13 nM/13 nM, 34 nM/13 nM/13 nM, 34 nM/13 nM/13 nM, 34 nM/13 nM/13 nM, 34 nM/13 nM/13 nM, 34 nM/13 nM/13 nM
In vitro	BIBF1120 inhibits PDGFR kinase activity of PDGFR alpha and PDGFR beta types with IC50 values of 59 nM and 65 nM, respectively. In addition, BIBF1120 suppresses the FGFR subtypes with IC50 of 60 nM, 37 nM and 108 nM for FGFR1, FGFR2, and FGFR3, respectively. BIBF1120 binds to the ATP-binding site in the cleft between the amino and carboxy terminal lobes of the kinase domain. The indolinone scaffold forms two hydrogen bonds with the backbone nitrogen of Cys919 and the backbone carbonyl oxygen of Glu917 in the hinge region. BIBF 1120 inhibits proliferation of PDGF-BB stimulated BRPs with EC50 of 79 nM in cell assays. BIBF1120 at concentrations as low as 100 nM blocks activation of MAPK after stimulation with 5% serum plus PDGF-BB. In cultures of human vascular smooth muscle cells (HUASMC), BIBF1120 prevents PDGF-BB stimulated proliferation with an EC50 of 69 nM. [1]
In vivo	In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.). This is evident in the magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and profound growth inhibition. [1]
Incubation Time	2 hours
Kinase Assay	[3], VEGFR2 Kinase Assay, The cytoplasmic tyrosine kinase domain of VEGFR2 (residues 797-1355 according to sequence deposited in databank SWISS-PROT P35968) is cloned into pFastBac fused to GST and extracted. Enzyme activity is assayed in the presence or absence of serial dilutions of BIBF1120 performed in 25% DMSO. Each microtiter plate contains internal controls such as blank, maximum reaction, and historical reference compound. All incubations are conducted at room temperature on a rotation shaker. 10 uL of each BIBF1120 dilution is added to 10 uL of diluted kinase (0.8 ug/mL VEGFR2, 10 mM Tris pH 7.5, 2 mM EDTA, and 2 mg/mL BSA) and preincubated for 1 hour. The reaction is started by addition of 30 uL of substrate mix containing 62.4 mM Tris pH 7.5, 2.7 mM DTT, 5.3 mM MnCl2, 13.3 mM Mg-acetate, 0.42 mM ATP, 0.83 mg/mL Poly-Glu-Tyr(4:1), and 1.7 ug/mL Poly-Glu-Tyr(4:1)-biotin and incubated for 1 hour. The reaction is stopped by addition of 50 uL of 250 mM EDTA, 20 mM HEPES, pH 7.4. 90 uL of the reaction mix is transferred to a streptavidin plate and incubated for 1-2 hours. After three washes with PBS the EU-labeled antibody, PY20 is added (recommended dilution 1:2000 of 0.5 mg/mL labeled antibody in DELFIA assay buffer). Excessive detection antibody is removed by three washes of DELFIA washing buffer. Then 10 minutes before measurement on the multilabel reader, each well is incubated with 100 uL of DELFIA enhancement solution.
Method	The cell lines HUVEC, HUASMC, and BRP are used for the assay. BIBF1120 is added to the cultures two hours before the addition of ligands. Cell lysates are generated. Western blotting is done using standard SDS-PAGE methods, loading 50 to 75 ug of protein per lane. Detection was facilitated by enhanced chemiluminescence. Total and phosphorylated mitogen-activated protein kinase (MAPK) is analyzed using monoclonal antibodies M3807 and M8159. Total Akt is detected using the corresponding polyclonal antibody and phosphorylated Akt (Ser473) is analyzed by using its monoclonal antibody. Monoclonal antibody is also used to detect cleaved caspase-3 while KDR (VEGFR2) protein is detected using a corresponding antibody.
Solubility (25C)	DMSO 6 mg/mL, Water <1 mg/mL, Ethanol 3 mg/mL
Information	Nintedanib is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM in cell-free assays. Phase 3.
Chemical Name	(Z)-methyl 3-((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylate

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