Bosutinib (SKI-606)Licensed by Pfizer 380843-75-4

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Molecular Weight:

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


Biological Activity


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. 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. 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.


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. 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. 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.


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)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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)

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 solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	100 mg/mL (188.51 mM)
		Water	<1 mg/mL (
		Ethanol	2 mg/mL (3.77 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

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