Choose Your Country or Region

SUNITINIB-AN INHIBITOR OF RECEPTOR TYROSINE KINASE

by Selleckchem | Jun 18 2012

A CHEMOTHERAPEUTIC AS MULTIKINASE INHIBITOR
Tyrosine kinases are the enzymes which act as mediators between different cells to facilitate variety of metabolic processes in cells. Since these tyrosine kinases play important role in processes e.g. division, survival, multiplication, differentiation, growth and death of cell, their inhibition have been found very promising target. Any type of modulation of these enzymes can cause the downstream regulation of the pathways controlled by them. This behaviour is being exploited as inhibitors of tyrosine kinases for chemotherapy. Many tyrosine kinase inhibitors are multi kinase inhibitors as they can inhibit more than one type of tyrosine kinase enzymes. VEGF pathway involvement in breast carcinoma and some other tyrosine kinases in other cancers made these enzymes a popular interest [1]. Different types of carcinomas are being successfully treated by using inhibitors of tyrosine kinase [2]. Tumours of stromal gastrointestinal are also being treated by administering inhibitors that can block various tyrosine kinases [3]. These inhibitors are also being used for the treatment of ALL (Acute Lymphoblastic Leukaemia) [4].

PROPERTIES OF SUNITINIB
Several researches are being done on Sunitinib which is a RTK inhibitor for therapy of cancer. Sunitinib structure revealed that it is a small molecule and Sunitinib solubility is 40mg/ml of DMSO while it is partial soluble in ethanol and water. Sunitinib stability is found to be near 2 years when stored at -20oC. Sunitinib supplier can provide Sunitinib to anyone who wants to buy Sunitinib under the trade name of either Sunitinib Sutent or Sunitinib malate at approximately 80$ per 1g. Structural studies showed that Sunitinib IC50 for VEGFR1 is 17nM, for PDFGR it is 2-3nM, for c-Kit it is 4-8 and for carboxamide it is 2nM.
A number of data is available which shows that Sunitinib acts as an inhibitor of multiple tyrosine kinases and have been shown to have both anti-proliferative and anti-cancer activity [5]. In clinical trials humans were tested for evaluation of its safety profile and as well as pharmacokinetic properties [6]and it favoured the successful use of Sunitinib inhibitor for therapy of cancer patients [7-8]. Very impressiveanti-angiogenic properties were shown by Sunitinib PDGFR inhibitor and as well as Sunitinib VEGFR inhibitors [9]. Strong promising results were obtained by the using FLT3 kinase inhibitor in case of NSCLC patients [10]. FLT3 TKI has also been administered as anti-VEGF therapy and for treatment of ALL conducted in clinical trials phase III [11-13]. Similarly against RCC Sunitinib c-kit inhibitor proved very efficient [14]. Human myeloma cancer is being treated by administration of this medicine [15].

CLINICAL TRIALS OF SUNITIB
Clinical trials of Phase I consisted of the study of mode of Sunitinib and it gave plentiful knowledge about its mechanism of action [16].Phase II clinical trials consisted of evaluation of its effect in patients of late stages of lung cancer in NSCLC [17-18].In clinical trials phase II it has shown positive results in the treatment of colorectal carcinoma [19]. In clinical levels of phase II an outstanding results were shown by Sunitinib in B-cell lymphoma patients [20-21].The significant effect of Sunitinib on ovarian cancer patients was reported in phase II [22].In phase I and II clinical trials Sunitinib was co-administrated with both Docetaxel and Prednisone in patients having prostate cancer and gave the positive results [23].The good records of Sunitinib’s efficiency and safety profile for GISTs (gastrointestinal stromal tumours) which further lead to the use of Sunitinib in GISTs patients under phase III clinical trials [24-25].
For treatment of RCC it is also being given to patients [26]. Worthwhile results were shown by Sunitinib in pancreatic neuroendocrine cancer patients[27].

REFERENCES:
1. Gasparini, G.e.a., Prognostic Value of Vascular Endothelial Growth Factor in Breast Cancer. The Oncologist, 2000
2. George, S., Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. Curr Oncol Rep., 2007.
3. Steeghs, N.e.a., Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments. Annals of Surgical Oncology, 2006.
4. Illmer, T.e.a., FLT3 Kinase Inhibitors in the Management of Acute Myeloid Leukemia. Clinical Lymphoma, Myeloma & Leukemia, 2007.
5. Christensen, J.G., A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Annals of Oncology, 2007.
6. Faivre, S.e.a., Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer. Journal of Clinical Oncology, 2006.
7. Abrams, T.J.e.a., SU11248 Inhibits KIT and Platelet-derived Growth Factor Receptor β in Preclinical Models of Human Small Cell Lung Cancer. Mol. Cancer Ther., 2003.
8. Hartmann, J.T.a.K., L., Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol., 2008.
9. Roskoski, R.e.a., Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochemical and Biophysical Research Communications, 2007.
10. Socinski, M.e.a., The Current Status and Evolving Role of Sunitinib in Non-small Cell Lung Cancer. Novel Agents in the Treatment of Lung Cancer, 2008.
11. Jain, R.K.e.a., Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology, 2006.
12. Stam, R.W.a.P., R., FLT3 Inhibitors as Therapeutic Agents in MLL Rearranged Acute Lymphoblastic Leukemia. New Agents for the Treatment of Acute Lymphoblastic Leukemia, 2011.
13. O'Farrell, A.e.a., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, 2003.
14. Ayllon, J.e.a., Long-Term Response and Postsurgical Complete Remissions After Treatment With Sunitinib Malate, an Oral Multitargeted Receptor Tyrosine Kinase Inhibitor, in Patients With Metastatic Renal Cell Carcinoma. Cancer Investigation, 2011.
15. Ikezoe, T.e.a., The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol. Cancer Ther., 2006.
16. Mena, C.e.a., Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib. Anti-Cancer Drugs, 2010.
17. Novello, S.e.a., Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. British Journal of Cancer, 2009.
18. Schneider, B.J.e.a., Phase II Trial of Sunitinib Maintenance Therapy After Platinum-Based Chemotherapy in Patients with Extensive-Stage Small Cell Lung Cancer. Journal of Thoracic Oncology, 2011.
19. Saltz, L.B.e.a., Phase II Trial of Sunitinib in Patients With Metastatic Colorectal Cancer After Failure of Standard Therapy. Journal of Clinical Oncology, 2007.
20. Buckstein, R.e.a., Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group. Leukemia & Lymphoma, 2011.
21. Burstein, H.J.e.a., Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane. Journal of Clinical Oncology, 2008.
22. al, B.J.J.e., A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Annals of Oncology, 2011.
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.
25. Marx, J.e.a., Encouraging results for second-generation antiangiogenesis drugs. Science, 2005.
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.