WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200560
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 received US FDA and EU European Medicines Agency approval on September 4, 2012 and 27 March, 2013 respectively for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.
MedKoo Cat#: 200560
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
Synonym: SKI606; SKI 606; SK-I606. 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|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
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.
|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.|
1: Redaelli S, Perini P, Ceccon M, Piazza R, Rigolio R, Mauri M, Boschelli F, Giannoudis A, Gambacorti-Passerini C. In vitro and in vivo identification of ABCB1 as an efflux transporter of bosutinib. J Hematol Oncol. 2015 Jul 7;8(1):81. PubMed PMID: 26149173.
2: Wang B, Cvetkovic D, Wang C, Chen L, Ma C. SU-E-T-668: Radiosensitizing Effect of Bosutinib On Prostate and Colon Cancers: A Pilot in Vitro Study. Med Phys. 2015 Jun;42(6):3490. doi: 10.1118/1.4925031. PubMed PMID: 26128331.
3: Takahashi N. [New treatment option for patient with CML-bosutinib]. Gan To Kagaku Ryoho. 2015 May;42(5):563-7. Japanese. PubMed PMID: 26054091.
4: Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, Turkina AG, Brümmendorf TH, Matczak E, Bardy-Bouxin N, Shapiro M, Turnbull K, Leip E, Cortes JE. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015 Jun 1. doi: 10.1002/ajh.24034. [Epub ahead of print] PubMed PMID: 26040495.
5: Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects. Drug Metabol Personal Ther. 2015 Mar;30(1):57-63. doi: 10.1515/dmdi-2014-0026. PubMed PMID: 25803093.
6: Doan V, Wang A, Prescott H. Bosutinib for the treatment of chronic myeloid leukemia. Am J Health Syst Pharm. 2015 Mar 15;72(6):439-47. doi: 10.2146/ajhp140221. Review. PubMed PMID: 25736937.
7: García-Gutiérrez V, Martinez-Trillos A, Lopez Lorenzo JL, Bautista G, Martin Mateos ML, Alvarez-Larrán A, Iglesias Pérez A, Romo Collado A, Fernandez A, Portero A, Cuevas B, Ruiz C, Romero E, Ortega F, Mata I, Tallón J, García Garay Mdel C, Ramirez Sánchez MJ, de Las Heras N, Giraldo P, Bobillo S, Guinea JM, Deben G, Valencia S, Sebrango A, Boqué C, Maestro B, Steegmann JL. Bosutinib shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth line. Results of the Spanish compassionate use program. Am J Hematol. 2015 May;90(5):429-33. doi: 10.1002/ajh.23973. Epub 2015 Mar 30. PubMed PMID: 25683327.
8: Randall N, Courville EL, Baughn L, Afrin L, Ustun C. Bosutinib, a Lyn/Btk inhibiting tyrosine kinase inhibitor, is ineffective in advanced systemic mastocytosis. Am J Hematol. 2015 Apr;90(4):E74. doi: 10.1002/ajh.23942. Epub 2015 Mar 2. PubMed PMID: 25641616.
9: Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, Yamamoto K, Miyamura K, Taniwaki M, Okada M, Kawaguchi T, Shibata A, Fujii Y, Ono C, Ohnishi K. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol. 2015 Feb;101(2):154-64. doi: 10.1007/s12185-014-1722-8. Epub 2014 Dec 25. PubMed PMID: 25540064.
10: Nguyen T, Hawkins E, Kolluri A, Kmieciak M, Park H, Lin H, Grant S. Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells. Leuk Res. 2015 Jan;39(1):65-71. doi: 10.1016/j.leukres.2014.10.009. Epub 2014 Nov 11. PubMed PMID: 25465126; PubMed Central PMCID: PMC4413916.
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.