BOSUTINIB- SRC INHIBITOR

by Selleckchem | Mar 26 2012

BOSUTINIB AND SRAC INHIBITORS
Although the RTKs are found to be very important and valuable molecules due to their role in signaling pathways, some other non RTKs (receptor tyrosine kinases) are also being found to play a key role in regulating the down stream signaling. An important example is SRC kinases family which phosphorylates the tyrosine residues of many membranes, nuclear and cytosolic proteins hence regulating the signaling pathways. Foe their property of making interconnections, SRC kinases is proved to be an attractive target for many inhibitor molecules for these signaling pathways and chemotherapy. Bosutinib SRC inhibitor, an example of such molecules which target not only SRC family kinases but also up regulate the ABL kinases, hence have a broad spectrum activity.

PROPERTIES OF BOSUTINIB:
Inhibitors to SRC kinase enzymes are most commonly used for treatment of tumors in solid forms [1] and promising results from various SRC inhibitors for different malignancies are getting popular. According to structure, Bosutinib consists of quinoline scaffold having different solubilizing groups around it and based upon quinazoline templates. For inhibition of SRC kinases and ABL kinases, Bosutinib IC50 is found to be 3.5 nM and 1.4 nM respectively [2]. One can purchase Bosutinib under the name Bosutinib SKI-606 with supplier Bosutinib for their laboratory and research use. Price
Bosutinib is almost around $50 for a 50 mg vial but the price may vary from company to company. Solubility of Bosutinib in ethanol and DMSO is 10 mg/ml and 33 mg/ml respectively while it is very poorly soluble in water. Stability of Bosutinib is about 2 years if stored at -20oC.

BOSUTINIB: USE IN CLINICS AND LABS
Bosutinib [3] is very novel and small size inhibitor molecule that promises a potent role against breast carcinoma cell lines in human [4]. Different in vivo experiments revealed its potency to affect growth, metastatic potential and invasion of tumor cells negatively [5]. In case of colorectal cancer cell lines it suppressed the growth of tumor and blocked the nuclear role of -catenin by reducing its binding capacity to TCF4 transcription factor [6]. Another drug known as Imatinib is found to be largely ineffective to remove stem cells of chronic myeloid leukemia while Bosutinib promised good suppression of growth of these progenitor cells. [7]
Clinical trials of Bosutinib are now very much in demand due to its better efficiency than Imatinib for inhibition of ABL kinase [8] and also warranting its efficacy in extreme disease conditions. It was also found to be successful in in vivo and in vitro treatment of cancer cells of chronic myeloid leukemia which were resistant to Imatinib [9]. A differential effect of Bosutinib, Dasatinib and Nilotinib was observed in Imatinib-resistant Philadelphia-positive cell lines of acute lymphoblastic leukemia having BCR/ABL mutations [10]. Effeciancy of Bosutinib was also reported in patienst of advanced or metastatic breast cancer cases which were resistant to chemotherapy [11].
Different clinical studies of Bosutinib are on different stages by Pfizer, the manufacturers. A phse I clinical study of Pfizer has assessed the formulation of clinical tablet, bioequivalence and effeciency of Bosutinib SRC inhibitor (NCT01374139). Some other studies by Pfizer include a clinical trial of phase II to determine the efficiency of combination therapy of Exemestane and Bosutinib as compared to roel of Exemestane alone in female patients of post menupause with breast carcinoma (NCT00793546). A phase II study compared Imatinib and Bosutinib with each other in Philadelphia positive CML patients (NCT00574873). All these results supported the value of Bosutinib in further clinical trials.

REFERENCES:
1. Kopetz, S.e.a., Src Continues Aging: Current and Future Clinical Directions. Clin Cancer Res, 2007.
2. Boschelli, F.e.a., Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. European journal of cancer, 2010.
3. Keller, R.e.a., Bosutinib. Small Molecules in Oncology, 2010.
4. Vultur, A.e.a., SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol. Cancer Ther, 2008.
5. Jallal, H.e.a., A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo. Cancer Res, 2007.
6. Coluccia, A.M.e.a., SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Cancer Res, 2006.
7. Konig, H.e.a., Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606. Blood, 2007.
8. Jabbour, E.e.a., New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. Semin. Hematol., 2007.
9. Puttini, M.e.a., In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res, 2006.
10. Redaelli, S.e.a., Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants Journal of Clinical Oncology, 2009.
11. Campone, M.e.a., 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. Annals of Oncology, 2011.