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.
J Virol. 2020 Feb 14;94(5):e01791-19.
Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use
Bosutinib purchased from AbMole
| Cell Experiment | |
|---|---|
| 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. |
| Concentrations | 0~1µM |
| Incubation time | 72h |
| Animal Experiment | |
|---|---|
| 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 |
| Administration | oral gavage |
| Molecular Weight | 530.45 |
| Formula | C26H29Cl2N5O3 |
| CAS Number | 380843-75-4 |
| Solubility (25°C) | DMSO |
| Storage | 2-8°C, protect from light |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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p60c-src substrate II is an efficient pentapeptide substrate for the tyrosine kinase pp60c-src. |
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