Bosutinib

ArtNr	S1014-5000
Hersteller	Selleckchem
CAS-Nr.	380843-75-4
Menge	5 g
Quantity options	10 mg 100 mg 1 g 10 g 10 mM/1 ml 200 mg 50 mg 5 g
Kategorie	Oncology Food Safety Allergenes Inhibitors & Compound Libraries Small Molecules By Organ Bladder Cancer Breast Cancer Heart & Blood Cancer
Typ	Inhibitors
Specific against	other
Smiles	CN1CCN(CC1)CCCOC2=C(C=C3C(=C2)N=CC(=C3NC4=CC(=C(C=C4Cl)Cl)OC)C#N)OC
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	SKI-606
Similar products	Bosutinib
Lieferbar
Manufacturer - Targets	SRC
Storage Conditions	2 years -80 in solvent
Molecular Weight	530, 45
Administration	Oral gavage
Animal Models	Nude female mice injected with K562 cells
Cell lines	Abl-MLV, Rat 2, KU812, K562, and MEG-01 cells
Clinical Trials	A Phase I study to compare the Bosutinib clinical tablet and clinical capsule and to investigate food effect on Bosutinib commercial formulation in healthy subjects has been completed.
Concentrations	Dissolved in DMSO, final concentrations ca.1 uM
Dosages	ca.150 mg/kg/day
Formulation	Suspended in 0.5% methocel/0.4% Tween 80
IC50	1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1]
In vitro	Bosutinib is selective for Src over non-Src family kinases with an IC50 of 1.2 nM, and potently inhibits Src-dependent cell proliferation with an IC50 of 100 nM. [1] Bosutinib significantly inhibits the proliferation of Bcr-Abl-positive leukemia cell lines KU812, K562, and MEG-01 but not Molt-4, HL-60, Ramos, and other leukemia cell lines, with IC50 of 5 nM, 20 nM and 20 nM, respectively, more potently than that of STI-571. Similar to STI-571, Bosutinib displays antiproliferative activity against the Abl-MLV-transformed fibroblasts with IC50 of 90 nM. Bosutinib ablates tyrosine phosphorylation of Bcr-Abl and STAT5 in CML cells and of v-Abl expressed in fibroblasts at the concentration of ca.50 nM, 10-25 nM and 200 nM, respectively, leading to the Bcr-Abl downstream signaling inhibition of Lyn/Hck phosphorylation. [2] Although unable to inhibit the proliferation and survival of breast cancer cells, Bosutinib significantly decreases the motility and invasion of breast cancer cells with IC50 of ca.250 nM, involved with an increase in cell-to-cell adhesion and membrane localization of beta-catenin. [3]
In vivo	Bosutinib (60 mg/kg/day) is active against Src-transformed fibroblasts xenografts and HT29 xenografts in nude mice with T/C of 18% and 30%, respectively. [1] Oral administration of Bosutinib for 5 days significantly suppresses K562 tumor growth in mice in a dose-dependent manner, with the large tumors eradicated at dose of 100 mg/kg and tumor free at 150 mg/kg without overt toxicity. [2] As being inactive against Colo205 xenografts in nude mice at 50 mg/kg twice daily, Bosutinib dosing at 75 mg/kg twice daily is necessary against Colo205 xenografts, and increasing the dose of Bosutinib has no additional benefit, in contrast to the significant dose-dependent ability against HT29 xenografts. [4]
Incubation Time	72 hours
Kinase Assay	The Src and Abl kinase assays, The Src kinase activity is measured in an ELISA format. Src (3 units/reaction), reaction buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 0.1 mM EGTA, 0.5 mM Na3VO4) and cdc2 substrate peptide are added to various concentration of Bosutinib and incubated at 30 C for 10 minutes. The reaction is started by the addition of ATP to a final concentration of 100 uM, incubated at 30 C for 1 hour and stopped by addition of EDTA. Instructions from the manufacturer are followed for subsequent steps. The Abl kinase assay is performed in a DELFIA solid phase europium-based detection assay format. Biotinylated peptide (2 uM) is bound to streptavidin-coated microtitration plates for 1.5 hours in 1 mg/mL ovalbumin in PBS. The plates are washed for 1 hour with PBS/0.1% Tween 80, followed by a PBS wash. The kinase reaction is incubated for 1 hour at 30C. Abl kinase (10 units) is mixed with 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 80 uM EGTA, 100 uM ATP, 0.5 mM Na3VO4, 1% DMSO, 1 mM HEPES (pH 7.0), 200 ug/mL ovalbumin and various concentration of Bosutinib. The reaction is stopped with EDTA at a final concentration of 50 mM. The reaction is monitored with Eu-labeled phosphotyrosine antibody and DELFIA enhancement solution.
Method	Cells are exposed to various concentrations of Bosutinib for 72 hours. Anchorage-independent proliferation of Abl-MLV-transformed fibroblasts is measured in 96-well ultra-low binding plates treated with Sigmacote to block residual cell attachment. Cell proliferation is measured with MTS or Cell-Glo. For the determination of cell cycle or cell death, cells are prepared for FACS analysis in the CycleTest Plus DNA reagent kit and analyzed on a fluorescence-activated cell sorter flow cytometer.
Solubility (25C)	DMSO 110 mg/mL, Water <1 mg/mL, Ethanol 54 mg/mL
Information	Bosutinib is a novel, dual Src/Abl inhibitor with IC50 of 1.2 nM and 1 nM in cell-free assays, respectively. Bosutinib also effectively decreases the activity of PI3K/AKT/mTOR, MAPK/ERK and JAK/STAT3 signaling pathways by blocking the phosphorylation levels of p-ERK, p-S6, and p-STAT3. Bosutinib promotes autophagy.
Chemical Name	4-(2, 4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

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