Bosutinib

Nude female mice injected with K562 cells

4-(2, 4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

Dissolved in DMSO, final concentrations ca.1 uM

ca.150 mg/kg/day

1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1]

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]

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.

530, 45

Data from [J Biol Chem, 2010, 285, 79777985], Bosutinib (SKI-606)purchased from Selleck, SFK inhibitors abrogate tyrosine phosphorylation associated with sperm capacitation. Mouse sperm were incubated in the absence or in the presence of SKI606 for 60 min in capacitating (cap, with HCO3) or non-capacitating media (NC, without HCO3). Western blot analyses were performed withanti-pY antibodies.

DMSO 110 mg/mL, Water <1 mg/mL, Ethanol 54 mg/mL