Bosutinib
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MedKoo CAT#: 200560

CAS#: 380843-75-4 (free base)

Description: Bosutinib, also known as SKI-606, is 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. Bosutinib was approved in 2012.


Chemical Structure

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Bosutinib
CAS# 380843-75-4 (free base)

Theoretical Analysis

MedKoo Cat#: 200560
Name: Bosutinib
CAS#: 380843-75-4 (free base)
Chemical Formula: C26H29Cl2N5O3
Exact Mass: 529.16475
Molecular Weight: 530.44
Elemental Analysis: C, 58.87; H, 5.51; Cl, 13.37; N, 13.20; O, 9.05

Price and Availability

Size Price Availability Quantity
200.0mg USD 150.0 Same day
500.0mg USD 250.0 Same day
1.0g USD 450.0 Same day
2.0g USD 750.0 Same day
5.0g USD 1650.0 2 Weeks
10.0g USD 2950.0 2 Weeks
20.0g USD 5250.0 2 Weeks
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Related CAS #: 918639-08-4 (hydrate)   380843-75-4 (free base)   2211052-79-6 (besylate)    

Synonym: SKI606; SKI 606; SK-I606. SK 606; SK-606; SK606; KIN 001-160; KIN001-160; KIN-001-160; KIN 001160; KIN-001160; KIN001160; Bosutinib; Brand name: Bosulif.

IUPAC/Chemical Name: 4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

InChi Key: UBPYILGKFZZVDX-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H29Cl2N5O3/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)

SMILES Code: N#CC1=C(NC2=CC(OC)=C(Cl)C=C2Cl)C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=C1

Appearance: Pale yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Bosutinib is a dual Src/Abl inhibitor with IC50s of 1.2 nM and 1 nM, respectively.
In vitro activity: This study examined the effects of bosutinib on colony formation and migration of HeLa cells, and determined whether bosutinib could induce HeLa cells apoptosis. The results showed that bosutinib inhibited HeLa cells proliferation and migration. Bosutinib significantly changed cell morphology, which indicated bosutinib-induced cytotoxicity in HeLa cells. But, the cytotoxic effects of bosutinib on HeLa cells were attenuated in the presence of over-expressed survivin, which indicated that bosutinib suppressed the viability of HeLa cells in a survivin-dependent manner. In addition, bosutinib increased the rate of apoptosis, suggesting that Src inhibition may also play a role in the process of apoptosis in HeLa cells. The results of Western blot revealed decreased expression of phospho-Src, Src, phospho-NF-κBp65, and survivin. Moreover, phospho-NF-κBp65 and survivin, but not phospho-Src and Src were upregulated in the survivin over-expressed group, suggesting that phospho-NF-κBp65 and survivin may play a role in bosutinib-induced HeLa cells apoptosis. Reference: Anat Rec (Hoboken). 2019 Dec;302(12):2193-2200. https://pubmed.ncbi.nlm.nih.gov/31569304/
In vivo activity: Bosutinib as adjunctive therapy to a balanced transfusion strategy was associated with reduced transfusion requirement, improved shock reversal, and reduced endothelial leakage with concomitant reduction in pulmonary oedema and lung injury when compared with a vehicle-treated control group. Bosutinib-treated rats also had less evidence of endothelial damage. Collectively, these data suggest that bosutinib can protect endothelial barrier integrity in traumatic bleeding, and can reduce transfusion requirements to restore circulation in a trauma model. IL-6 levels were lower in bosutinib-compared with vehicle-treated rats with traumatic injury. The immunomodulatory effects of bosutinib have been shown in mouse-derived macrophages, in which bosutinib reduced IL-6 production. Less endothelial damage might lead to a reduced inflammatory response as well. The bosutinib-treated group required less transfusion products (and hence less plasma and platelets) than the vehicle group, whereas coagulation parameters in the ROTEM assays did not differ. In addition to an effect on endothelial barrier function, bosutinib may also reduce endothelial-driven coagulopathy in this model. Further evaluation is necessary to pinpoint the effects of bosutinib on trauma-induced coagulopathy, including platelet function and coagulation factors. Reference: Br J Anaesth. 2021 May;126(5):958-966. https://bjanaesthesia.org/article/S0007-0912(21)00090-8/fulltext

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 54.76 103.24
Ethanol 14.09 26.56

Preparing Stock Solutions

The following data is based on the product molecular weight 530.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Yu L, Guo W, Liu L, Zhang G, Zhang F, Qu Y, Liu Y, Li H, Li H. Bosutinib Acts as a Tumor Inhibitor via Downregulating Src/NF-κB/Survivin Expression in HeLa Cells. Anat Rec (Hoboken). 2019 Dec;302(12):2193-2200. doi: 10.1002/ar.24269. Epub 2019 Oct 9. PMID: 31569304. 2. Segrelles C, Contreras D, Navarro EM, Gutiérrez-Muñoz C, García-Escudero R, Paramio JM, Lorz C. Bosutinib Inhibits EGFR Activation in Head and Neck Cancer. Int J Mol Sci. 2018 Jun 21;19(7):1824. doi: 10.3390/ijms19071824. PMID: 29933569; PMCID: PMC6073167. 3. Kleinveld DJB, Botros L, Maas MAW, Kers J, Aman J, Hollmann MW, Juffermans NP. Bosutinib reduces endothelial permeability and organ failure in a rat polytrauma transfusion model. Br J Anaesth. 2021 May;126(5):958-966. doi: 10.1016/j.bja.2021.01.032. Epub 2021 Mar 6. PMID: 33685634. 4. Botros L, Pronk MCA, Juschten J, Liddle J, Morsing SKH, van Buul JD, Bates RH, Tuinman PR, van Bezu JSM, Huveneers S, Bogaard HJ, van Hinsbergh VWM, Hordijk PL, Aman J. Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity. J Cell Sci. 2020 May 14;133(9):jcs240077. doi: 10.1242/jcs.240077. PMID: 32198280.
In vitro protocol: 1. Yu L, Guo W, Liu L, Zhang G, Zhang F, Qu Y, Liu Y, Li H, Li H. Bosutinib Acts as a Tumor Inhibitor via Downregulating Src/NF-κB/Survivin Expression in HeLa Cells. Anat Rec (Hoboken). 2019 Dec;302(12):2193-2200. doi: 10.1002/ar.24269. Epub 2019 Oct 9. PMID: 31569304. 2. Segrelles C, Contreras D, Navarro EM, Gutiérrez-Muñoz C, García-Escudero R, Paramio JM, Lorz C. Bosutinib Inhibits EGFR Activation in Head and Neck Cancer. Int J Mol Sci. 2018 Jun 21;19(7):1824. doi: 10.3390/ijms19071824. PMID: 29933569; PMCID: PMC6073167.
In vivo protocol: 1. Kleinveld DJB, Botros L, Maas MAW, Kers J, Aman J, Hollmann MW, Juffermans NP. Bosutinib reduces endothelial permeability and organ failure in a rat polytrauma transfusion model. Br J Anaesth. 2021 May;126(5):958-966. doi: 10.1016/j.bja.2021.01.032. Epub 2021 Mar 6. PMID: 33685634. 2. Botros L, Pronk MCA, Juschten J, Liddle J, Morsing SKH, van Buul JD, Bates RH, Tuinman PR, van Bezu JSM, Huveneers S, Bogaard HJ, van Hinsbergh VWM, Hordijk PL, Aman J. Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity. J Cell Sci. 2020 May 14;133(9):jcs240077. doi: 10.1242/jcs.240077. PMID: 32198280.

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1: Cui Z, Li B, Zhang Y, He J, Shi X, Wang H, Zhao Y, Yao L, Ai D, Zhang X, Zhu Y. Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation. Hypertension. 2021 Nov;78(5):1527-1540. doi: 10.1161/HYPERTENSIONAHA.121.17548. Epub 2021 Oct 4. PMID: 34601968; PMCID: PMC8516812.

2: Yilmaz S, Alkan T, Ballar Kirmizibayrak P. A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity-induced PARylation in SIN1-mediated neurotoxicity. J Biochem Mol Toxicol. 2021 Sep 14:e22915. doi: 10.1002/jbt.22915. Epub ahead of print. PMID: 34519134.

3: Mahdavi KD, Jordan SE, Barrows HR, Pravdic M, Habelhah B, Evans NE, Blades RB, Iovine JJ, Becerra SA, Steiner RA, Chang M, Kesari S, Bystritsky A, O'Connor E, Gross H, Pereles FS, Whitney M, Kuhn T. Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor. Neurol Clin Pract. 2021 Jun;11(3):e294-e302. doi: 10.1212/CPJ.0000000000000918. PMID: 34484904; PMCID: PMC8382351.

4: Rea D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina AG, Kim DW, Apperley JF, Abdo A, Fogliatto LM, Kim DDH, le Coutre P, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Sasaki K, Chee L, Garcia-Gutierrez V, Cortes J, Aimone P, Allepuz A, Quenet S, Bédoucha V, Hochhaus A. A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs. Blood. 2021 Aug 18:blood.2020009984. doi: 10.1182/blood.2020009984. Epub ahead of print. PMID: 34407542.

5: Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–. Bosutinib. 2021 Aug 16. PMID: 29999903.

6: Nakajima R, Matsuo T, Sumiyoshi R, Saito S, Yamamoto T, Matsumoto K, Akiyama N, Ooi J, Ota Y, Shirafuji N, Tashiro H. Extramedullary blast crisis in a chronic myeloid leukaemia patient after achieving a major molecular response with bosutinib. Br J Haematol. 2021 Aug 10. doi: 10.1111/bjh.17771. Epub ahead of print. PMID: 34378212.

7: Muresan B, Mamolo C, Cappelleri JC, Postma MJ, Heeg B. Cost-Effectiveness of Bosutinib for the Treatment of Adult Patients with Chronic Phase Chronic Myeloid Leukemia in the Second-Line Setting. Appl Health Econ Health Policy. 2021 Jul 12. doi: 10.1007/s40258-021-00666-0. Epub ahead of print. PMID: 34250585.

8: Levy M, Xie L, Wang Y, Neumann F, Srivastava S, Naranjo D, Xu J, Zhang Q, Dalal M. Comparison of incidence/occurrence of cardiovascular events between ponatinib vs bosutinib among patients with at least one prior line of tyrosine kinase inhibitors in chronic myeloid leukemia in a community setting in the United States. Cancer Treat Res Commun. 2021;28:100424. doi: 10.1016/j.ctarc.2021.100424. Epub 2021 Jun 18. PMID: 34198039.

9: Prajapati PB, Bagul N, Kalyankar G. Implementation of DoE and Risk-Based Enhanced Analytical Quality by Design Approach to Stability Indicating RP-HPLC Method for Stability Study of Bosutinib. J AOAC Int. 2021 Jun 8:qsab078. doi: 10.1093/jaoacint/qsab078. Epub ahead of print. PMID: 34100929.

10: Liu QS, Ass'ad NA, Arana Yi C. Bosutinib-associated interstitial lung disease and pleural effusion: A case report and literature review. Clin Case Rep. 2021 May 7;9(5):e03164. doi: 10.1002/ccr3.3164. PMID: 34094551; PMCID: PMC8145267.

11: Wall TP, Crowley PD, Buggy DJ. The Effect of Lidocaine and Bosutinib on 4T1 Murine Breast Cancer Cell Behaviour In Vitro. Anticancer Res. 2021 Jun;41(6):2835-2840. doi: 10.21873/anticanres.15064. PMID: 34083273.

12: Jain N, Maiti A, Ravandi F, Konopleva M, Daver N, Kadia T, Pemmaraju N, Short N, Kebriaei P, Ning J, Cortes J, Jabbour E, Kantarjian H. Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia. Am J Hematol. 2021 Aug 1;96(8):1000-1007. doi: 10.1002/ajh.26238. Epub 2021 May 28. PMID: 33991360.

13: Hall KH, Brooks A, Waller EK. Overcoming TKI resistance in a patient with chronic myeloid leukemia using combination BCR-ABL inhibition with asciminib and bosutinib. Am J Hematol. 2021 Aug 1;96(8):E293-E295. doi: 10.1002/ajh.26231. Epub 2021 May 25. PMID: 33971041.

14: Chuah C, Koh LP, Numbenjapon T, Zang DY, Ong KH, Do YR, Ohkura M, Ono C, Viqueira A, Cortes JE, Brümmendorf TH. Efficacy and safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the Asian subpopulation of the phase 3 BFORE trial. Int J Hematol. 2021 Jul;114(1):65-78. doi: 10.1007/s12185-021-03144-4. Epub 2021 Apr 13. PMID: 33851349.

15: Hirasawa T, Kikuchi M, Shigeta K, Takasaki S, Sato Y, Sato T, Ogura J, Onodera K, Fukuhara N, Onishi Y, Maekawa M, Mano N. High-throughput liquid chromatography/electrospray ionization-tandem mass spectrometry method using in- source collision-induced dissociation for simultaneous quantification of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in human plasma. Biomed Chromatogr. 2021 Aug;35(8):e5124. doi: 10.1002/bmc.5124. Epub 2021 Apr 18. PMID: 33772839.

16: Takakuwa T, Sakai R, Koh S, Okamura H, Nanno S, Nakashima Y, Nakane T, Koh H, Hino M, Nakamae H. High-grade B-cell lymphoma developed during the treatment of chronic myeloid leukemia with bosutinib. Clin Case Rep. 2021 Jan 13;9(3):1344-1349. doi: 10.1002/ccr3.3770. PMID: 33768841; PMCID: PMC7981704.

17: Abumiya M, Takahashi N, Takahashi S, Yoshioka T, Kameoka Y, Miura M. Effects of SLC22A2 808G>T polymorphism and bosutinib concentrations on serum creatinine in patients with chronic myeloid leukemia receiving bosutinib therapy. Sci Rep. 2021 Mar 18;11(1):6362. doi: 10.1038/s41598-021-85757-7. PMID: 33737618; PMCID: PMC7973796.

18: Muresan B, Mamolo C, Cappelleri JC, Leip E, Viqueira A, Heeg B. An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia. Curr Med Res Opin. 2021 May;37(5):801-809. doi: 10.1080/03007995.2021.1896489. Epub 2021 Apr 2. PMID: 33733983.

19: Hu S, Xie D, Zhou P, Liu X, Yin X, Huang B, Guan H. LINCS gene expression signature analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1. Int J Mol Med. 2021 May;47(5):72. doi: 10.3892/ijmm.2021.4905. Epub 2021 Mar 11. PMID: 33693953; PMCID: PMC7952247.

20: Kleinveld DJB, Botros L, Maas MAW, Kers J, Aman J, Hollmann MW, Juffermans NP. Bosutinib reduces endothelial permeability and organ failure in a rat polytrauma transfusion model. Br J Anaesth. 2021 May;126(5):958-966. doi: 10.1016/j.bja.2021.01.032. Epub 2021 Mar 6. PMID: 33685634; PMCID: PMC8258973.

Bosutinib

200.0mg / USD 150.0


Additional Information

According to http://www.bosutinib.org/, Bosutinib is a third generation tyrosine kinase inhibitor. It is being tested in clinical trials and looks very promising. It has been useful in patients whose leukemia is resistant to both first and second generation tyrosine kinase inhibitors. It is a dual kinase inhibitor. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis (cell death). Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. It seems to cause fewer side effects because it more selectively inhibits the faulty proteins in the leukemic cells and doesnÂ’t affect similar proteins in normal cells as much as the earlier drugs do. Bosutinib is going through the phases of drug testing in the United States necessary to eventually obtain FDA approval. In the first study, reported in 2007, 69 patients with either CML or ALL whose cancer was resistant to other drugs were treated with bosutinib, which is also known as SKI606. This study determined the best dose for the drug, which is 500 mg. a day. Bosutinib is given orally. Phase II involved 98 patients with CML, many of whom had become resistant to either imatinib or nilatib and dasatinib. 23 patients resistant to imatinib had a complete response to bosutinib. Complete response is defined as a normal blood count. These 23 patients represented 74% of the imatinib-resistant patients. The researchers were able to evaluate more thoroughly a group of 36 patients to look at their Philadelphia chromosomes. Of the 36, 15 had a major response; 12 of the 15 had a complete response, meaning that they no longer had the Philadelphia chromosome.