SORAFENIB-AS A MULTIKINASE INHIBITOR

by Selleckchem | Jun 08 2012

SORAFENIB

For receiving extracellular or intracellular stimulus numerous types of non-receptor and receptor tyrosine kinases are present in cells which are capable of conducting inhibitory and initiatory action on different signalling pathways. Defect of any type in these processes can cause cancer. The kinases which are involved in the over-expression or under expression of gene that are cause of cancer can be used as target for cancer therapy. Different types of kinases are being inhibited by employing only one inhibitor. Due to the involvement of abnormal tyrosine kinase in the development of cancer inhibitors of tyrosine kinases are being developed and studied to use it as for the treatment of cancer. Clinical trials of different inhibitors have shown outstanding results. Among these inhibitors one important inhibitor is Sorafenib inhibitor which has shown to inhibit kinases excluding respective VEGFR. Similarly Raf pathway/ERK/MEK pathway have been found inhibited by the administration of Sorafenib Raf inhibitor.

Sorafenib PDGFR inhibitor is being developed and distributed by Onyx and as well as Bayer which are among the famous pharmaceutical companies. The structural studies of Sorafenib indicated that it contains bi-aryl urea which is a derivative and available in market under the trade name of Bay 43-9006. It is available in 500mg packaging of approximately $88 and Sorafenib supplier can supply Sorafenib to anyone who wants to buy Sorafenib.200mg/ml of DMSO is the maximum Sorafenib solubility and it is insoluble in water and as well as in ethanol. Storage at -20°C gives stability to Sorafenib for approximately 2 years. Sorafenib IC50 is found to be 38nM for inhibition of B-RafV599E, 22 nM for B-Rafwt and 6nM for Raf. A lot of research work is being carried out to study the various properties of Sorafenib.

SORAFENIB: PRECLINICAL AND CLINICAL STUDIES

Sorafenib Nexavar is being evaluated for its efficiency to treat numerous cancer types in various clinical and pre-clinical trials. Sorafenib ERK inhibitor was administered in kidney cancer cells and long term survival and no progression was seen [1]. In a study combinatorial therapies were conducted in which patients having kidney carcinoma were exposed to radio and chemotherapy were administered with Sorafenib MEK inhibitor & as well as surgery was done and they have been shown to support each other effect [2].This drug has also shown increased survival rate in patients of liver cancer [3]. Phase II clinical trials were consisted of patients suffering from MTC or medullary thyroid cancer were administered with it and 85% efficiency was seen [4]. Androgen free patients of prostate cancer showed the same results when treated with Sorafenib [5]. For the treatment of patients suffering from liver cancer, NSCLC and melanoma, Sorafenib was co-administered with Paclitaxel-Carboplatin, Gefitinib and Doxorubicin and it has shown outstanding results related to its efficiency and safety [6].

SORFENIB: CLINICAL USE

For the treatment of HCC and kidney cancer Sorafenib has been approved for marketing and use. FDA approved it for treatment of renal cell carcinoma in 2005 and for hepatocellular carcinoma in 2008. For marketing it got approved in 2006 for RCC and in 2007 for HCC. For the treatment of relapsed Glioblastoma or GBM Sorafenib has been co-administered with other medicines. So phase II and I clinical trials that were consisted of co-administration of Sorafenib with Temsirolimus. Similarly it was administered to non-responsive patients of thyroid cancer in phase II. The complementing behaviour of Anastrozole and Sorafenib were analysed in phase II clinical studies on breast cancer patients having menopause conducted by NCI or National Cancer Institute. The patients of NSCLC who were gone through failed therapy of EGFR inhibitor were administered with Sorafenib and evaluated by Chinese research society in Phase II clinical trials.

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.