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Bosutinib

Bosutinib 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. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer: Wyeth Inc.

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 doesn’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.

1: Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, Chiorean EG, Springett GM, Abbas R, Agarwal S, Bardy-Bouxin N, Hsyu PH, Leip E, Turnbull K, Zacharchuk C, Messersmith WA. Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors. Clin Cancer Res. 2011 Dec 16. [Epub ahead of print] PubMed PMID: 22179664.

2: Abbas R, Hug BA, Leister C, Sonnichsen D. A randomized, crossover, placebo- and moxifloxacin-controlled study to evaluate the effects of bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects. Int J Cancer. 2011 Nov 8. doi: 10.1002/ijc.27348. [Epub ahead of print] PubMed PMID: 22065400.

3: Trask PC, Cella D, Besson N, Kelly V, Masszi T, Kim DW. Health-related quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant chronic phase chronic myeloid leukemia. Leuk Res. 2011 Oct 28. [Epub ahead of print] PubMed PMID: 22036634.

4: Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. PubMed PMID: 21865346.

5: Campone M, Bondarenko I, Brincat S, Hotko Y, Munster PN, Chmielowska E, Fumoleau P, Ward R, Bardy-Bouxin N, Leip E, Turnbull K, Zacharchuk C, Epstein RJ. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann Oncol. 2011 Jun 23. [Epub ahead of print] PubMed PMID: 21700731.

6: Abbas R, Hug BA, Leister C, Gaaloul ME, Chalon S, Sonnichsen D. A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol. 2012 Jan;69(1):221-7. Epub 2011 Jun 21. PubMed PMID: 21691746.

7: Gleixner KV, Mayerhofer M, Cerny-Reiterer S, Hörmann G, Rix U, Bennett KL, Hadzijusufovic E, Meyer RA, Pickl WF, Gotlib J, Horny HP, Reiter A, Mitterbauer-Hohendanner G, Superti-Furga G, Valent P. KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib. Blood. 2011 Aug 18;118(7):1885-98. Epub 2011 Jun 16. PubMed PMID: 21680801.

8: Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D. Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects. J Clin Pharmacol. 2011 Dec;51(12):1721-7. Epub 2010 Dec 8. PubMed PMID: 21148045.

9: Keller G, Schafhausen P, Brummendorf TH. Bosutinib: a dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukemia. Expert Rev Hematol. 2009 Oct;2(5):489-97. Review. PubMed PMID: 21083014.

10: Hebbard L, Cecena G, Golas J, Sawada J, Ellies LG, Charbono A, Williams R, Jimenez RE, Wankell M, Arndt KT, DeJoy SQ, Rollins RA, Diesl V, Follettie M, Chen L, Rosfjord E, Cardiff RD, Komatsu M, Boschelli F, Oshima RG. Control of mammary tumor differentiation by SKI-606 (bosutinib). Oncogene. 2011 Jan 20;30(3):301-12. Epub 2010 Sep 6. PubMed PMID: 20818417; PubMed Central PMCID: PMC3000443.

11: Yin XJ, Xu GH, Sun X, Peng Y, Ji X, Jiang K, Li F. Synthesis of bosutinib from 3-methoxy-4-hydroxybenzoic acid. Molecules. 2010 Jun 11;15(6):4261-6. PubMed PMID: 20657439.

12: Redaelli S, Boschelli F, Perini P, Pirola A, Viltadi M, Gambacorti-Passerini C. Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib. Leukemia. 2010 Jun;24(6):1223-7. Epub 2010 May 6. PubMed PMID: 20445575.

13: Rabbani SA, Valentino ML, Arakelian A, Ali S, Boschelli F. SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol Cancer Ther. 2010 May;9(5):1147-57. Epub 2010 Apr 27. PubMed PMID: 20423991.

14: Boschelli F, Arndt K, Gambacorti-Passerini C. Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer. 2010 Jul;46(10):1781-9. Review. PubMed PMID: 20399641.

15: Keller G, Schafhausen P, Brümmendorf TH. Bosutinib. Recent Results Cancer Res. 2010;184:119-27. Review. PubMed PMID: 20072835.

16: Hegedus C, Ozvegy-Laczka C, Apáti A, Magócsi M, Német K, Orfi L, Kéri G, Katona M, Takáts Z, Váradi A, Szakács G, Sarkadi B. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol. 2009 Oct;158(4):1153-64. Epub 2009 Sep 28. PubMed PMID: 19785662; PubMed Central PMCID: PMC2785536.

17: Messersmith WA, Rajeshkumar NV, Tan AC, Wang XF, Diesl V, Choe SE, Follettie M, Coughlin C, Boschelli F, Garcia-Garcia E, Lopez-Rios F, Jimeno A, Hidalgo M. Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts. Mol Cancer Ther. 2009 Jun;8(6):1484-93. Epub 2009 Jun 9. PubMed PMID: 19509264.

18: Mologni L, Cleris L, Magistroni V, Piazza R, Boschelli F, Formelli F, Gambacorti-Passerini C. Valproic acid enhances bosutinib cytotoxicity in colon cancer cells. Int J Cancer. 2009 Apr 15;124(8):1990-6. PubMed PMID: 19123474.

19: Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, Gambacorti-Passerini C, Boschelli F. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009 Jan 20;27(3):469-71. Epub 2008 Dec 15. PubMed PMID: 19075254.

20: Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. Epub 2008 Nov 27. PubMed PMID: 19039322.