Bosutinib (SKI-606) Licensed by Pfizer

Bosutinib (SKI-606) is a novel, dual Src/Abl inhibitor with IC50 of 1.2 nM and 1 nM, respectively.

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Bosutinib (SKI-606) Chemical Structure

Bosutinib (SKI-606) Chemical Structure
Molecular Weight: 530.45

Validation & Quality Control

Customer Reviews(3)

Quality Control & MSDS

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  • Research Area
  • Bosutinib (SKI-606) Mechanism
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Bosutinib (SKI-606) is a novel, dual Src/Abl inhibitor with IC50 of 1.2 nM and 1 nM, respectively.
Targets Abl [2] Src [1]
IC50 1 nM 1.2 nM
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 ~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 ~250 nM, involved with an increase in cell-to-cell adhesion and membrane localization of β-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]
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

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 μM, 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 μM) 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 30°C. Abl kinase (10 units) is mixed with 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 80 μM EGTA, 100 μM ATP, 0.5 mM Na3VO4, 1% DMSO, 1 mM HEPES (pH 7.0), 200 μg/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.

Cell Assay:

[2]

Cell lines Abl-MLV, Rat 2, KU812, K562, and MEG-01 cells
Concentrations Dissolved in DMSO, final concentrations ~1 μM
Incubation Time 72 hours
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.

Animal Study:

[2]

Animal Models Nude female mice injected with K562 cells
Formulation Suspended in 0.5% methocel/0.4% Tween 80
Dosages ~150 mg/kg/day
Administration Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Boschelli DH, et al. J Med Chem, 2001, 44(23), 3965-3977.

[2] Golas JM, et al. Cancer Res, 2003, 63(2), 375-381.

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Chemical Information

Download Bosutinib (SKI-606) SDF
Molecular Weight (MW) 530.45
Formula

C26H29Cl2N5O3

CAS No. 380843-75-4
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 100 mg/mL (188 mM)
Water <1 mg/mL (<1 mM)
Ethanol 2 mg/mL (3 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

Research Area

Customer Reviews (3)


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Rating
Source J Virol 2011 85, 2296–2303. Bosutinib (SKI-606) purchased from Selleck
Method Endothelial cell permeability assay
Cell Lines Human endothelial cells
Concentrations 0-10 μM
Incubation Time 15-60 min
Results Figure C defines concentrations of kinase inhibitors which block ANDV-induced EC permeability approximately 50% (IC50s). IC50s of bosutinib are 100 nM and 10 μM. we next assessed the abilities of bosutinib to block ANDV-induced permeability at its IC50s from 15 to 60 min after VEGF addition, we find that bosutinib inhibited ANDV-induced permeability up to 40 to 50% but only at IC50s of 10 μM(Figure D).

Click to enlarge
Rating
Source J Biol Chem 2010 285, 7977–7985. Bosutinib (SKI-606) purchased from Selleck
Method Western blot
Cell Lines Mouse sperm
Concentrations 0-50 μM
Incubation Time 60 min
Results In the case of SKI606, a sharp inhibitory effect was observed at 50 μM.

Click to enlarge
Rating
Source Dr. Pablo E.Visconti from University of Massachusetts. Bosutinib (SKI-606) purchased from Selleck
Method Western blot
Cell Lines sperm
Concentrations 50 μΜ
Incubation Time
Results PKA and tyrosine phosphorylation was rescue by Ser/Thr phosphatase inhibitors SKI-606 and SU6656.

Product Citations (7)

Tech Support & FAQs

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