Bosutinib

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WARNING: This product is for research use only, not for human or veterinary use.

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.

Price and Availability

Bosutinib, purity > 98%, is in stock. The same day shipping out after order is received.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 200560Name: BosutinibCAS#: 380843-75-4Chemical Formula: C26H29Cl2N5O3Exact Mass: 529.16475Molecular Weight: 530.44Elemental 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

Technical Data

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.  

References

 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, CortesJE. 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.