Bosutinib
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.
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.
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.
| Chemical | |
|---|---|
| CAS Num | 380843-75-4 |
| Chemical Formula | C26H29Cl2N5O3 |
| Molecular Weight | 530.44 |
| IUPAC Chemical Name | 4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile |
| Exact Mass | 529.16475 |
| 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 |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | N#CC1=C(NC2=CC(OC)=C(Cl)C=C2Cl)C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=C1 |
| Biological | |
| Targets and Effects | BCR-ABL |
| Pathways | Apoptosis |
| Physical | |
| 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). |
| Shelf Life | >2 years if stored properly |
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