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Bosutinib hydrate (SKI606; KIN001160; SKI-606; KIN-001160; Bosulif), the mono-hydrated form of bosutinib, is a synthetic quinolone derivative and dual kinase inhibitor targeting both Abl and Src kinases with potential antineoplastic activity. In 2012, bosutinib was licensed for the treatment of adult patients with chronic myelogenous leukemia (CML), which is chromosome-positive (Ph+).
| Targets |
Csk (IC50 = 314 nmol/L); Abl kinase (IC50 = 2.4 nmol/L)
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| ln Vitro |
Bosutinib has an IC50 of 1.2 nM for Src family kinases and an IC50 of 100 nM for potently inhibiting Src-dependent cell proliferation. [1] With IC50 values of 5 nM, 20 nM, and 20 nM, respectively, bosutinib more potently inhibits the proliferation of Bcr-Abl-positive leukemia cell lines KU812, K562, and MEG-01 but not Molt-4, HL-60, Ramos, or other leukemia cell lines. Bosutinib exhibits antiproliferative activity against Abl-MLV-transformed fibroblasts with an IC50 of 90 nM, which is comparable to STI-571. At concentrations of approximately 50 nM, 10–25 nM, and 200 nM, respectively, bosutinib inhibits the tyrosine phosphorylation of Bcr-Abl and STAT5 in CML cells as well as v-Abl expressed in fibroblasts. This results in the inhibition of Lyn/Hck phosphorylation by Bcr-Abl downstream signaling.[2] With an IC50 of approximately 250 nM, bosutinib significantly reduces the motility and invasion of breast cancer cells, albeit it is unable to inhibit the proliferation and survival of these cells. This effect is linked to an increase in cell-to-cell adhesion and β-catenin membrane localization.[3]
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| ln Vivo |
Bosutinib (60 mg/kg/day) is effective against HT29 xenografts and Src-transformed fibroblast xenografts in nude mice with T/C values of 18% and 30%, respectively.[1] When mice are given Bosutinib orally for five days, the growth of K562 tumors is significantly suppressed. This effect is dose-dependent, with large tumors being completely removed at a dose of 100 mg/kg and tumor free at 150 mg/kg without causing overt toxicity.[2] Whereas bosutinib's significant dose-dependent ability against HT29 xenografts contrasts with its inactive nature against Colo205 xenografts in nude mice at 50 mg/kg twice daily, bosutinib's dosing at 75 mg/kg twice daily is necessary against Colo205 xenografts, and increasing the dose has no additional benefit.[4]
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| Enzyme Assay |
ELISA is used to measure Src kinase activity. Reaction buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 0.1 mM EGTA, 0.5 mM Na3VO4), Src (3 units/reaction), and cdc2 substrate peptide are added to varying concentrations of bosutinib and incubated for 10 minutes at 30 °C. A final concentration of 100 μM of ATP is added to initiate the reaction, which is then incubated for an hour at 30 °C before being stopped with the addition of EDTA. The next steps are carried out in accordance with the manufacturer's instructions. Using a DELFIA solid phase europium-based detection assay format, the Abl kinase assay is carried out. For 1.5 hours, 1 mg/mL ovalbumin in PBS is used to bind biotinylated peptide (2 μM) to streptavidin-coated microtitration plates. A PBS wash is performed after an hour of washing the plates with PBS/0.1% Tween 80. One hour at 30°C is spent heating the kinase reaction. The following mixture contains 10 units of Abl kinase: 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 different concentrations of bosutinib. EDTA, at a final concentration of 50 mM, is used to stop the reaction. Equine phosphotyrosine antibody labeled with Eu and DELFIA enhancement solution are used to track the reaction.
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| Cell Assay |
Bosutinib is applied to cells at different concentrations for a duration of 72 hours. In 96-well ultra-low binding plates treated with Sigmacote to prevent residual cell attachment, the anchorage-independent proliferation of Abl-MLV-transformed fibroblasts is assessed. Cell-Glo or MTS are used to measure cell proliferation. Using the CycleTest Plus DNA reagent kit, cells are prepared for FACS analysis and examined on a fluorescence-activated cell sorter flow cytometer to determine whether the cells are in the cell cycle or have died.
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| Animal Protocol |
Nude female mice injected with K562 cells
~150 mg/kg/day Oral gavage |
| References | |
| Additional Infomation |
Bosutinib hydrate is a hydrate that is the monohydrate form of anhydrous bosutinib. It has a role as an antineoplastic agent and a tyrosine kinase inhibitor. It contains a bosutinib.
Bosutinib Monohydrate is the monohydrate form of bosutinib, a synthetic quinolone derivative and dual kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. Abl kinase is upregulated in the presence of the abnormal Bcr-abl fusion protein which is commonly associated with chronic myeloid leukemia (CML). Overexpression of specific Src kinases is also associated with the imatinib-resistant CML phenotype. See also: Bosutinib (has active moiety). Drug Indication Bosulif is indicated for the treatment of adult patients with: newlyâdiagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML). CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. |
| Molecular Formula |
C26H31CL2N5O4
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|---|---|
| Molecular Weight |
548.465
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| Exact Mass |
547.175
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| Elemental Analysis |
C, 56.94; H, 5.70; Cl, 12.93; N, 12.77; O, 11.67
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| CAS # |
918639-08-4
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| Related CAS # |
Bosutinib;380843-75-4;Bosutinib-d8
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| PubChem CID |
11990828
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| Appearance |
White to off-white solid powder
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| LogP |
4.423
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
37
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| Complexity |
734
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N#CC1C(NC2C(Cl)=CC(Cl)=C(OC)C=2)=C2C(C=C(C(=C2)OC)OCCCN2CCN(C)CC2)=NC=1.O
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| InChi Key |
BXPOSPOKHGNMEP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H29Cl2N5O3.H2O/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27;/h11-14,16H,4-10H2,1-3H3,(H,30,31);1H2
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| Chemical Name |
4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile;hydrate
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| Synonyms |
KIN-001160; SK606; KIN001-160; SKI 606; KIN 001160; KIN001160; SKI606; SK-I606; SK-606; SK 606; KIN 001-160; KIN-001-160; trade name: Bosulif.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8233 mL | 9.1163 mL | 18.2325 mL | |
| 5 mM | 0.3647 mL | 1.8233 mL | 3.6465 mL | |
| 10 mM | 0.1823 mL | 0.9116 mL | 1.8233 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03654768 | Active Recruiting |
Drug: Bosutinib Drug: Dasatinib |
Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive |
SWOG Cancer Research Network | October 24, 2018 | Phase 2 |
| NCT04655391 | Withdrawn | Drug: Bosutinib Monohydrate Drug: Decitabine |
Recurrent Acute Myeloid Leukemia | City of Hope Medical Center | June 25, 2022 | Phase 1 |
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