SORAFENIB-AS A MULTIKINASE INHIBITOR

by Selleckchem | May 21 2012

SORAFENIB
Various kinds of receptor and non-receptor kinase enzymes are there in the cells that are responsible of carrying out the signaling pathways of initiation or inhibition of cascades after getting intra or extracellular stimulus. Any sort of defect in this process may cause cancer. Inhibition of kinase enzymes to prevent some mal-expressed or over-expressed gene causing tumor is found to be an effective approach. Many multiple kinases can be inhibited by using a single inhibitor. Various types of inhibitors against these kinase proteins are being discovered and studied in order to develop some effective anti-cancer therapy, as many of the tyrosine kinase abnormalities used to become the cause of development of cancer. Many of them are giving promising results in their clinical trials. An important example of these inhibiting drugs is Sorafenib VEGFR inhibitor that has been found to inhibit the protein kinases except respective VEGFR. In the same way Sorafenib Raf inhibitor also an important drug used for the inhibition of MEK/ERK/Raf pathway.
Well known pharmaceutical companies named Bayer and Onyx are the developers and distributers of the drug Sorafenib PDGFR inhibitor. Sorafenib structure reveals that it is a bi-aryl urea derivative and marketed under the brand name Bay 43-9006. Doctors or researchers can purchase Sorafenib from Sorafenib supplier by paying around $88 for a 500 mg vial. Sorafenib solubility was found to be good in DMSO and is up to 200 mg/mL while it is completely insoluble in ethanol and water. Sorafenib can be stable even for two years when stored under -20 °C. For the inhibition of mutant B-Rafwt, B-RafV599E and Raf-, Sorafenib IC50 is observed to be 22, 38 and 6 nM respectively. To unveil the further properties of this drug, loads of research is being made.

SORAFENIB: PRECLINICAL AND CLINICAL STUDIES
Many preclinical and clinical trials are carried out to check the efficiency of Sorafenib Nexavar against different types of cancers. In patients suffering from clear renal cell cancer, Sorafenib was used as an ERK inhibitor and a prolonged survival was observed in them without any further progression [1]. A stage IV multimodal strategy was employed in case of renal cell carcinoma which involves surgery, chemo and radiotherapy by using Sorafenib MEK inhibitor and these combinational therapies resulted in synergistic effects [2]. This medicine has improved the rate of survival in hepatocellular carcinoma patients [3]. When used against the patients of medullary thyroid cancer or MTC either sporadic or metastatic under clinical trials phase II, it gave 85% promising results [4]. In case of androgen free prostate cancer patients Sorafenib gave exactly similar results [5]. Sorafenib has been used in combination with some other medicines like Gefitinib, Paclitaxel-Carboplatin and Doxorubicin against solid tumor patients of NSCLC, melanoma and hepatocellular carcinoma, and very low toxicity level and good efficiency was observed [6].

SORFENIB: CLINICAL USE
Sorafenib has got approval for its use and marketing against advanced renal cell carcinoma and HCC. It has approved from Food and Drug Administration for using against advanced RCC in 2005 and against HCC in 2008. The marketing approval against renal cancer was gained in 2006 while against HCC was gained in 2007. Sorafenib clinical trials were carried for its use in combination with some other drugs for recurrent kinds of tumors like GBM or Glioblastoma. For this reason Sorafenib was used combined with Temsirolimus in clinical trials phase I and II. In the same way a clinical analysis of phase II against unresponsive thyroid cancer patients was also made. National Cancer Institute as known as NCI is also carrying out a phase II study against after menopause-metastatic breast cancer patients (NCT00217399) to check the synergistic effects of Sorafenib and Anastrozole. The effects of sorafenib in NSCLC patients under phase II are under study these days by a Chinese research society, these are the patients suffered the failed attempts of Epidermal Growth Factor Receptor inhibitor (NCT00922584).

REFERENCES:
1. Escudier, B.e.a., Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med., 2007.
2. Walid, M.S.a.J., K.W., Successful treatment of a brain-metastasized renal cell carcinoma. Ger Med Sci, 2009.
3. Keating, G.M.a.S.A., Sorafenib: A Review of its Use in Advanced Hepatocellular Carcinoma. Drugs, 2009.
4. Lam, E.T.e.a., Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol., 2010.
5. Dahut, W.L.e.a., A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer. Clin Cancer Res, 2008.
6. Takimoto, C.H.a.A., A. et al, Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemotherapy and Pharmacology, 2008.