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Bosutinib(SKI-606)

Catalog No. S1014 Name Selleck Chemicals
CAS Number 380843-75-4 Website http://www.selleckchem.com
M. F. C26H29Cl2N5O3 Telephone (877) 796-6397
M. W. 530.44616 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 72460

SYNONYMS

IUPAC name
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-2-carbonitrile
IUPAC Traditional name
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-2-carbonitrile
Synonyms
SKI-606

DATABASE IDS

CAS Number 380843-75-4

PROPERTIES

Target SRC
Salt Data Free Base
Solubility DMSO
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description Solid tumours,Breast cancer
Biological Activity
Description Bosutinib (SKI-606) is a novel, dual Src/Abl inhibitor with IC50 of 1.2 nM and 1 nM, respectively.
Targets

Src

Abl

IC50

1.2 nM [1]

1 nM [2]

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]
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.
Features
Combination Therapy
Description The combination of Bosutinib and Imatinib produces a synergistic inhibitory effect on proliferation of Bcr-Abl-positive cell lines resistant to imatinib, although to a lesser degree than observed in imatinib-sensitive lines. [5] Bosutinib in combination with ABT-263 has synergistic effects on inducing the anoikis of LC-KJ and HCC827 cells. [6]
Protocol
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
Methods

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
Doses ~150 mg/kg/day
Administration Oral gavage
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.
[3] Vultur A, et al. Mol Cancer Ther, 2008, 7(5), 1185-1194.
[4] Golas JM, et al. Cancer Res, 2005, 65(12), 5358-5364.
[5] Redaelli S, et al. Leukemia, 2010, 24(6), 1223-1227.
[6] Sakuma Y, et al. Oncol Rep, 2011, 25(3), 661-667.