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SUNITINIB-AN RTK INHIBITOR

by Selleckchem | Jul 17 2012

SUNITINIB: INHIBITS MULTIPLE KINASES
There are different cell signaling processes in metabolic resources which supervise other important cellular functions. One of the most vital types of cellular processes is tyrosine kinase pathways which control many other important pathways like cellular proliferation, growth, apoptosis and cell survival etc. When these tyrosine kinases are over expressed the abnormal cell growth has been noted, which is the reason of many lethal diseases such as cancer. The approach of designing inhibitors for tyrosine kinases is one of the leading fields in drug designing against cancers. It is possible that a single inhibitor can inhibit the functions of multiple tyrosine kinases. One of the examples of cancer associated with tyrosine kinase is breast cancer where VEGF pathway gets abnormal [1]. Many carcinomas has been handled by using inhibitors of tyrosine kinases [2] and one example is gastrointestinal stromal cancer where such inhibitors are being used [3] and one another example is ALL (acute Lymphoblastic Leukemia) treatment [4].

PROPERTIES OF SUNITINIB
A good quality example of tyrosine kinase inhibitors is Sunitinib which is actively employed for cancer treatment and also for anti-cancer targeting. The Sunitinib solubility is up to 40mg/ml in dimethyle sulfoxide (DMSO) but it is partially soluble in ethanol and water. As the Sunitinib structure depicts it is a small molecule. This inhibitor is stable for a period of 2 years if placed at -20 oC. One can purchase Sunitinib from any of the Sunitinib supplier by paying 80$ for a 1g vial. Sunitinib IC50 is 2, 17, 4-8 and 2-3nM for carboxamide, VEGFR1, c-Kit and PDGFR respectively. In market Sunitinib Sutent or Sunitinib malate is available.
A sufficient research has been done on Sunitinib where it is used as an anti-proliferative and anti-cancer agent which inhibits multiple tyrosine kinases [5]. During clinical trials the safety profile and pharmacokinetics has been analyzed on humans [6] and it reported as a potent anti-cancer drug for the treatment of cancer [7-8]. It has been noted that Sunitinib PDGFR inhibitor have very powerful results on angiogenesis [9]. Sunitinib c-kit inhibitor has shown quite effective results when used against NSCLC (non-small cell lung cancer) [10]. During clinical trial phase III it has been used against VEGF for the treatment of ALL or acute lymphoblastic leukemia [11-13]. Sunitinib 341031-54-7 is also a potential therapeutic for renal cancer treatment [14]. The tumor which metastasized into human blood is also treated with this inhibitor [15].

SUNITINIB: CLINICAL STUDIES
In order to study the mechanism of action of Sunitinib, Sunitinib clinical trial phase I was done [16]. During phase II of clinical trials researchers reported the mechanism that how this compound acts on NSCLC patients [17-18]. And also in patients with colorectal cancer Sunitinib was found as potent drug during phase II trials [19]. Another study during the same phase B-cell lymphoma patients were treated with Sunitinib and encouraging results obtained [20-21] and when applied on ovarian cancer patients this molecule showed remarkable results during phase II of clinical trials [22].
Sunitinib has been used in combination too for example in the treatment of prostate cancer it was co-administered with Docetaxel and Prednisone which results in positive results [23]. The clinical trials study phase III was involved in the studies of GISTs patients where Sunitinib’s efficiency and safety profile was studied in stromal tumors of gastrointestinal and encouraging results were obtained [24-25]. This is also used for renal cancer and pancreatic endocrine cancer treatment where Sunitinib acted as a potent anti cancer agent [26-27].

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.

Cat.No.	Product Name	Information
S1042	Sunitinib malate	Sunitinib malate is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM in cell-free assays, and also inhibits c-Kit. Sunitinib Malate effectively inhibits autophosphorylation of Ire1α. Sunitinib Malate increases both death receptor and mitochondrial-dependent apoptosis.
S1148	Docetaxel	Docetaxel, an analog of paclitaxel, is an inhibitor of depolymerisation of microtubules by binding to stabilized microtubules.