PAZOPANIB: LATEST VEGFR INHIBITOR

by Selleckchem | Sep 11 2012

PAZOPANIB:
A very famous pharmaceutical company named GlaxoSmithKline is the manufacturer of a very important anticancer drug Pazopanib Votrient also called Pazopanib VEGFR inhibitor and is selling it by the market name Votrient. Pazopanib is a quick source of anti-angiogenic activity that inhibits VEGF, R1, VEGFR2 and VEGFR3 in conjunction with the β subtypes and c-kit RTKs and PDGFR-a. Pazopanib is such a tiny structure that got fame only in previous years by showing its remarkable activity in various sorts of cancers. Pazopanib VEGFR-PDGFR inhibitor is indeed one amongst those necessary inhibitors that are currently approved for the utilization at clinical level [1]. Pazopanib structure reveals the presence of a sulfonamide group. One can purchase Pazopanib from supplier Pazopanib by paying Pazopanib price that is around $100 per a 25mg packing under the market name Votrient or GW786034. Its price might vary among the suppliers. Pazopanib solubility is ideally detected in DMSO however it is fully insoluble in water and ethanol. It is stability is increased for nearly 2 years if preserved at -20oC. The studies revealed that Pazopanib IC50 value for VEGF-R1 is 10 nM, for VEGF-R2 is 30 nM and for VEGF-R3 is 47nM. Pazopanib IC50 values for few related kinases for example PDFGR-beta is 82 nM, c-fms is 146 nM, c-kit is 74 nM and FGFR1 is 140 nM.

PAZOPANIB: CLINICAL TRIALS
For the production and its studies in clinical trials were supported by the Pazopanib Votrient initial screening and discovery [2]. The urge to carry out its clinical studies and its market value was increased by its characteristics properties such as tolerability, safety, adaptability and outstanding pharmacokinetics profile [3]. The equal concentration of Pazopanib revealed by pre-clinical trials has contributed to carry clinical trials phase I consisting of its study as anti-neoplastic drug and pharmacodynamics properties [4]. Pazopanib GW786034 targeted endothelial and also tumor cells when in vitro cell culture studies were conducted [5]. When administered in mince suffering from CNV or choroidalneovascularization it showed specific and outstanding targeting [6]. Molecular imaging method was employed to assess Pazopanib by non-invasive technique [7] and it can be further used. Pazopanib c-kit inhibitor was shown to target the melanoma cell lines and breast cancer cells expressing protein called B-Raf in a recent study performed [8]. It showed promising results in the treatment of NSCLC when co-administered with Lapatinib [9]. Pediatric solid tumors in mice were treated by co-administration of Pazopanib with Topotecan [10].

EFFECTIVE CLINICAL TRIALS OF PAZOPANIB
Bone and tissue sarcoma were administered with Pazopanib GW786034 in phase III clinical trials [11]. Phase II clinical trials consisted of patients suffering from kidney cancer were administered with it and showed fruitful results [12]. Outstanding results were shown by Pazopanib when it was administered in patients of advanced stages of kidney cancer of phase II trials [13].Although it is very effective when administered alone but its co-administration with Lapatinib has increased its value among the combinational therapies [14]. Brilliant efficiency was shown by Pazopanib when administered in patients suffering from prostate cancer that are castration-sensitive in clinical levels of phase II [15]. When co-administered with Cyclophosphamide in patients of pre-treated or relapsed patients of ovarian cancer it showed fruitful results in II and I clinical trials [16]. The study of patients having metastasized or relapsed nasopharyngeal cancer and belonging from Asia was conducted in Pazopanib clinical trial of phase II [17].

REFERENCES:
1. Bukowski, R.e.a., Pazopanib. Nature Reviews Drug Discovery, 2010.
2. Harris, P.e.a., Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor. J. Med. Chem., 2008.
3. Sonpavde, S.a.H., TE, Pazopanib: A novel multitargeted tyrosine kinase inhibitor. Current Oncology Reports, 2007.
4. Kumar, R.e.a., Mol Cancer Therap. 2007.
5. Podar, K.e.a., The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. PNAS, 2006.
6. Takahashi, K.e.a., The Multi-targeted Kinase Inhibitor Pazopanib Causes Suppression and Regression of Choroidal Neovascularization. Arch Ophthalmol., 2009.
7. Blankenberg, F.e.a., Noninvasive Assessment of Tumor VEGF Receptors in Response to Treatment with Pazopanib: A Molecular Imaging Study. Transl Oncol., 2010.
8. Gril, B.e.a., The B-Raf Status of Tumor Cells May Be a Significant Determinant of Both Antitumor and Anti-Angiogenic Effects of Pazopanib in Xenograft Tumor Models. PLoS ONE, 2011.
9. Olaussen, K.e.a., Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines. Oncogene, 2009.
10. Kumar, S.e.a., Metronomic Oral Topotecan with Pazopanib Is an Active Antiangiogenic Regimen in Mouse Models of Aggressive Pediatric Solid Tumor. Clin Cancer Res, 2011.
11. Sleijfer, S.e.a., Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients with Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). Journal of Clinical Oncology, 2009.
12. Hutson, T.e.a., Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology, 2010.
13. Sternberg, C.e.a., Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. Journal of Clinical Oncology, 2010.
14. Sloan, B.a.S., NS, Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs, 2008.
15. Ward, J.e.a., A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study. Prostate Cancer and Prostatic Diseases, 2011.
16. Eichbaum, M.e.a., The PACOVAR-trial: A phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer. BMC Cancer, 2011.
17. Lim, W.e.a., Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma. Clin Cancer Res, 2011.

Cat.No.	Product Name	Information
S3012	Pazopanib	Pazopanib (GW786034) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms/CSF1R with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively. Pazopanib induces cathepsin B activation and autophagy.
S2111	Lapatinib	Lapatinib is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM in cell-free assays, respectively. Lapatinib induces ferroptosis and autophagic cell death.
S1231	Topotecan HCl	Topotecan HCl is a topoisomerase I inhibitor for MCF-7 Luc cells and DU-145 Luc cells with IC50 of 13 nM and 2 nM in cell-free assays, respectively. Topotecan HCl induces autophagy and apoptosis.