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SUNITINIB: A MULTI-KINASE ENZYME INHIBITOR

by Selleckchem | May 24 2012

TYROSINE KINASE INHIBITORS
Tyrosine kinase enzymes are very important amongst the diversified world of proteins involving the signal transduction process for their role in various processes like inhibition or activation of genes expression responsible for cell growth, cell division, cell differentiation and cell death. Abnormalities in these tyrosine kinases are leading cause of in the disruption in above mentioned functions stimulating the tumor development. The inhibition of tyrosine kinase enzyme is an attractive target when there is the disruption in any cell cycle regulatory enzyme affected by the tyrosine kinase in case of any kind of cancer. So these enzymes are the attractive target for anti-tumor drugs as they are those that start the function. Tyrosine kinase inhibitors are having the ability of affecting different kinds of tyrosine kinase enzymes hence called as multikinase inhibitors and they may be non-receptor or receptor kinases. If the type of kinase involving in the cancer condition is known, like for VEGF involved in the breast cancer, the medicine for choice must be a TKI [1]. Tyrosine kinase inhibitors exhibited promising results when were used against gastrointestinal stromal tumors or GISTs [2] and for the solid form tumors [3]. For ALL or acute lymphoblastic leukemia, the FLT3 TKIs are in use for treatment [4].

SUNITINIB: PROPERTIES
Sunitinib is one good example of Tyrosine kinase inhibitors while Sunitinb VEGFR inhibitor and Sunitinib PDGFR inhibitor are the further examples. Sunitinib structure reveals that it has a carboxamide group and is being used usually these days. For VEGFR1, R2 and R3, Sunitinib IC50 is 2 nM, 9 nM and 17 nM while for PDGF-R and c-Kit inhibitor it is 8 nM and 4 nM respectively. One can purchase Sunitinib by paying Sunitinib price around $80 for a 1 gm vial. Sunitinib price may vary from supplier to supplier. Sunitinib solubility in DMSO is almost 40 mg/ml but it is poorly soluble in ethanol and water. Sunitinib is stable for 2 years when stored at -20°C.
A great amount of data is available about the pre clinical research on Sunitinib that proved it as strong anti- angiogenic and anti-tumor [5]. The pharmacokinetic properties of this drug and its safety profile were studied for human also [6]. These studies favor the use of Sunitinib as Sunitinib c-Kit inhibitor [8] in cancer patients successfully [7]. The use of Sunitinib as an anti-angiogenic inhibitor medicine has encouraged by the research on it as a Sunitinib PDGFR inhibitor and Sunitinib VEGFR inhibitor [9]. It has also studied as a FLT3 inhibitor in NSCLC patients [10]. Sunitinib has undergone clinical studies phase III as a VEGF Tyrosine Kinase Inhibitor [11], FLT3 TKI [13] and ALL TKI [12]. It has shown very remarkable results against renal cell carcinoma [14] and various other types of hematologic malignant tumors in human [15].

SUNITINIB: CLINICAL TRIALS
Sunitinib clinical trial was carried out on patients suffering from different kinds of cancers and has shown very encouraging results. The mode of action of this drug was clearly understood in the clinical trials phase I [16]. Sunitinib is now under phase II clinical trials in case of many types of cancers like Non-small cell lung cancer or NSCLC [17] and advanced lung cancer [18], B cell lymphoma [20], ovarian cancer [22], breast cancer [21] and colorectal cancer [19]. A combined treatment of Sunitinib and Prednisone and Docetaxel was also carried out against prostate cancer patients and very remarkable results were obtained from clinical trials phase I and phase II [23]. The efficacy and safety of this medicine was studied in patients of GISTs [24] and were also successfully studied in clinical phase III for it [25]. It has also undergone phase III studies in renal cell carcinoma patients [26] and the pancreatic neuroendocrine tumors [27].

REFERENCES:
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23. Zurita, A.J.e.a., Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Annals of Oncology, 2011.
24. Demetri, G.D.e.a., Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. The Lancet, 2006.
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26. Eichelberg, C.e.a., Sequential Use of the Tyrosine Kinase Inhibitors Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma: A Retrospective Outcome Analysis. European Urology, 2008.
27. Raymond, R.e.a., Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med, 2011.