SORAFENIB-A MULTIKINASE INHIBITOR

by Selleckchem | Apr 24 2012

SORAFENB
Different types of receptor or non-receptor kinases are there in the cells that are involved in the signaling process in order initiate or inhibit a process after getting extra/intracellular stimulus. Any defect in this system may lead to cancer. Inhibition of Kinases in order to prevent any over-expressed or mal-expressed gene causing cancer is a very effective strategy. There are multiple types of kinases which can be inhibited by a single type of inhibitor. As various Tyrosine kinase aberrations become the reason for developing cancers, many inhibitors against these proteins are being researched in search of developing an effective anti-cancer therapy. Any of them are undergoing clinical trials and are giving promising results. One of the examples of such inhibitors is Sorafenib VEGFR inhibitor that has also been seen to inhibit protein kinases other than respective VEGFR. Similarly Sorafenib Raf inhibitor may be used effectively for inhibition of MEK/Raf/ERK pathway.
Sorafenib PDGFR inhibitor has been developed by the pharmaceutical companies Bayer and Onyx and is marketed. Sorafenib structure is a derivative of bi-aryl urea and the brand name of the drug is Bay 43-9006. Researchers or doctors can buy Sorafenib 500 mg package in around $88. Sorafenib solubility is upto 200 mg/mL in DMSO but is insoluble in water and ethanol. Sorafenib stability can be maintained for upto two years if stored at -20 oC. Sorafenib IC50 for inhibition of mutant B-RafV599E, B-Rafwt , and Raf-1 and is 38, 22, 6 nM respectively. Further research is being made in order to unveil more characteristics of the drug.

STUDY AT PRECLINICAL AND CLINICAL LEVEL
A lot of preclinical and clinical trials are being made in order to check the efficacy of Sorafenib against cancer of different types. Sorafenib when used as erk inhibitor was studied in patients of clear renal cell carcinoma and prolonged their survival without further progression [1]. In case of RCC (renal cell carcinomas) stage IV multimodal approach was used that employed surgery, radio and chemotherapy by Sorafenib MEK inhibitor these combinatorial modes of treatment gave synergistic effects [2]. The drug improved the survival rate of patients who were suffering from hepatocellular carcinoma [3]. In case of (MTC) medullary thyroid cancer patients whether metastatic or sporadic, use of Sorafenib gave promising results in 85 % of patients in phase II clinical trials [4]. Similar results have been obtained in phase II trial in the patients of prostate cancer who are androgen free [5]. Low toxicity with good efficacy has been observed in combinatorial therapy of Sorafenib with other drugs like Doxorubicin, Gefitinib and Paclitaxel-Carboplatin against the patients of solid tumors in hepatocellular carcinoma, Non-small cell lung cancer and melanoma [6].

APPROVAL FOR CLINICAL USAGE
Sorafenib has earned the approval for its usage and marketing for advanced renal carcinoma and hepatocellular carcinoma (HCC). Approval from FDA i.e., Food and Drug Administration had been obtained in 2005 for advanced renal carcinoma and in 2008 for HCC. Marketing approval for renal carcinoma was obtained in 2006 while for its use against HCC it was obtained in 2007. Sorafenib clinical trials are being made in order to use this drug in combination with other drugs for recurrent types of cancers like Glioblastoma (GBM). For this purpose Sorafenib is being studied in combination with Temsirolimus in phase I/II. Similarly clinical trial in phase III is being made for patients of unresponsive thyroid cancer. NCI i.e., National Cancer Institute is also studying the synergistic effects of Sorafenib with Anastrozole in phase II trial on metastatic breast cancer patients after menopause (NCT00217399). A Chinese society is studying the effects of the drug in NSCLC (Non-small cell lung cancer patients) in phase II clinical study after failed attempts of (EGFR) Epidermal Growth Factor Receptor inhibitor in these patients (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.