Bosutinib (SKI-606) is an active inhibitor of Bcr-Abl in several chronic myelogenous leukemia cell lines and transfectants. The IC50 values are in the low nanomolar range, which is 10- to 100-fold lower than those obtained with imatinib. Bosutinib has activity in cells where resistance to imatinib resulted from BCR-ABL gene amplification and in three of four Bcr-Abl point mutants examined. In in vivo experiments bosutinib retains activity in models where resistance is not caused by mutations, as well as in cells carrying the Y253F, E255K, and D276G mutations. Bosutinib binds to a different conformation of Bcr-Abl than does imatinib.
|Cell lines||Abl-MLV, Rat 2, MEG-01, and K562 cell lines|
|Preparation method||cell lines were obtained from the American Type Culture Collection. The KU812 line was obtained from the European Collection of Cell Cultures. K562 and KU812 cell lines were maintained in RPMI 1640 supplemented with 10% FCS, glutamine, and nonessential amino acids (Life Technologies, Inc.). Rat 2 and Abl-MLV-transformed Rat 2 cells were maintained in high-glucose DMEM supplemented with 10% FCS. For proliferation assays, cells were exposed to compound for 72 h, and relative proliferation was measured with either 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium (Promega) or Cell-Glo (Promega). Anchorage-independent proliferation of Abl-MLV-transformed fibroblasts was measured in 96-well ultra-low binding plates (Costar) treated with Sigmacote (Sigma) to block residual cell attachment. Data analysis for IC50 calculations was performed with the LSW Data Analysis Package plug-in for Excel (Microsoft). For biochemical assays, cells were incubated with compound or DMSO alone for 4 h. Cells were prepared for FACS analysis as described in the CycleTest Plus DNA reagent kit (Becton Dickinson) and analyzed on a fluorescence-activated cell sorter flow cytometer.|
|Animal models||K562 Xenografts in nude mice|
|Formulation||in a 0.2-ml suspension with 0.5% methocel/0.4% Tween 80.|
|Dosages||75 mg/kg twice a day|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial.
Cortes et al. J Clin Oncol. 2012 Sep 4. PMID: 22949154.
Ascending Single-Dose Study of the Safety Profile, Tolerability, and Pharmacokinetics of Bosutinib Coadministered With Ketoconazole to Healthy Adult Subjects.
Abbas et al. Clin Ther. 2012 Aug 9. PMID: 22884766.
Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain.
Levinson et al. PLoS One. 2012;7(4):e29828. PMID: 22493660.
Bosutinib for the treatment of chronic myeloid leukemia in chronic phase.
Quintás-Cardama et al. Drugs Today (Barc), 2012 Mar;48(3):177-88. PMID: 22462037.
Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure.
Khoury et al. Blood. 2012 Apr 12;119(15):3403-12. PMID: 22371878.
SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer.
Kim et al. Clin Cancer Res. 2012 Mar 1;18(5):1281-90. PMID: 22271876.
Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors.
Daud et al. Clin Cancer Res. 2012 Feb 15;18(4):1092-100. PMID: 22179664.
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