SORAFENIB- A MULTIKINASE TYROSINE INHIBITOR

by Selleckchem | Jun 27 2012

SORAFENIB: INTRODUCTION

Various kinds of non-receptor tyrosine kinases or receptor tyrosine kinases (RTKs) are available in the cells which are employed in responding to intra or extracellular stimulusby carrying out either initiatory or inhibitory action on various signaling pathways. Any sort of problem in this process may cause cancer. Inhibition of kinase enzymes to prevent some mal-expressed or over-expressed gene causing cancer is found to be an effective tool. Inhibition of various kinases is being done by using single inhibitor. Since malfunctioned tyrosine kinases are involved in onset of cancer, research is being done on their inhibitors for cancer therapy.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. When Sorafenib Raf inhibitor was given Raf/MEK/ERK pathway was found inhibited.

Bayer and Onyx are well known pharmaceutical companies which are producing Sorafenib PDGFR inhibitor. Sorafenib structure revealed that it contained bi-aryl urea derivative and commercially available as Bay 43-9006. Sorafenib is supplied by Sorafenib supplier at the rate of $88 per 500mg vial to researchers or scientists who want to buy Sorafenib. 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 unleashmore properties of this drug, huge research is being made.

PRECLINICAL AND CLINICAL TRIALS OF SORAFENIB
Different pre-clinical and clinical trials are being conducted on Sorafenib Nexavarfor treatment of various cancers. Prolonged survival and regression was seen in renal cancer cells when treated with Sorafenib ERK inhibitor [1].A 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]. When given to hepatocellular carcinoma patients survival rate was seen increased [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].

CLINICAL USE OF SORAFENIB

Sorafenib got approval for therapy of RCC and HCC. In 2005 and 2008 it got approved by FDA for RCC and HCC respectively. 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 tumours like GBM or Glioblastoma. So it was administered with Temsirolimus in phase I and II trials. Non-responsive patients suffering from thyroid cancer were treated with it in clinical trials phase II. National Cancer Institute as known as NCI is also carrying out a phase II study against after menopause-metastatic breast cancer patients to check the synergistic effects of Sorafenib and Anastrozole. In phase II non-small cell lung cancer patients who showed resistance to EGFR inhibitor were treated with Sorafenib and reported by Chinese research society.

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.