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SORAFENIB: THE MULTIKINASE INHIBITOR

by Selleckchem | Mar 13 2012

SORAFENIB INTRODUCTION:

Sorafenib is a member of the class of compounds referred to as tyrosine kinase inhibitors. Developed originally as a Raf inhibitor the Sorafenib RAF inhibitor proved to be effective against more than one tyrosine kinase. Sorafenib demonstrated abilities to inhibit both tumor progression kinases and tumor angiogenesis kinases.[1;2] As a direct result of the multiple targeting of this compound the Sorafenib PDGFR inhibitor has demonstrated activity in a wide range of cancer types such as renal cell carcinoma[3], breast cancer [4;5], hepatocellular carcinoma [6] and colorectal carcinoma [7;8]. Sorafenib is currently one of only 10 tyrosine kinase inhibitors approved for clinical use under FDA rulings (2005 – advanced renal cell carcinoma, RCC; 2007 – in inoperable Hepatocellular carcinoma, HCC), in addition Sorafenib has been approved by the European Medicines agency for use in HCC and RCC where first line therapy has failed.

Sorafenib (Nexavar) Chemical Structure

SORAFENIB - PHARMACOLOGY AND PROPERTIES:

Sorafenib suppliers market it under the brand name of Nexavar and its development is controlled in tandem by Onyx and Bayer pharmaceutical companies, although its original name was BAY 43-9006. To buy Sorafenib – the free base is widely commercially available at research grade and Sorafenib price for a 10 mg vial range from $50 to 150 depending on supplier. The p-toluenesulfonate salt is also commercially available at research grade and is significantly cheaper than the free base with prices ranging from $135 – 150 for a 1 g vial.

Sorafenib structure shows that it is based on a bi-aryl urea derivative but like most tyrosine kinase inhibitors Sorafenib solubility in water and ethanol is extremely poor, however Sorafenib can be dissolved in DMSO up to 200 mg/ml. When stored at -20^oC, sorafenib stability for the free base is for 2 years, no details are given on stability in solution.

Sorafenib IC50 against VEGFR-2, PDGFR-ß, Raf, FGFR-1, BRAF (wild type) and V599E (mutated BRAF) tyrosine kinase inhibition is 90 ± 15, 20 ± 6, 6 ± 3, 580 ± 100, 22 ± 6 and 38 ± 9 nM respectively.

Sorafenib Preclinical:

Sorafenib was first reported in 2002 under the code BAY 43-9006 as part of a preclinical screening of bis-aryl ureas. This class of compounds was investigated based on computer design and simulation as being potential inhibitors of the Raf-1 kinase. Sorafenib (as it later came to be known) was selected from the screening process after demonstrating inhibitory potential against Raf (IC50 – 12 nM).[9] Additional to Raf-1 Sorafenib was shown to inhibit ERK ½ in a biomarker analysis of the tumors from a phase 1 study.[10] In a separate investigation Sorafenib VEGFR inhibitor exhibit significant activity in suppressing tumor progression and neovascularization. Targets Sorafenib demonstrated activity against included vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT [11]. These results were entirely consistent with the inhibition of the RAF/MEK/ERK pathway but it should be noted not all models responded. Surprisingly Sorafenib also demonstrated activity against mutant KRAS and BRAF as well as wild BRAF in several different cancer types (breast, colon and pancreatic) [12]. With such significant results Sorafenib was fast tracked to the clinical phase 1 testing.

Sorafenib – Clinical phase 1, 2 and 3 trials

The first reported phase 1 trial for Sorafenib is in patient with advanced solid tumors where positive indications were recorded for survival and tumor reduction.[13] This was followed up with a phase 1 trials in combination with Doxorubicin or Irinotecan in patients with solid tumors again with positive indications for Sorafenib.[14;15] In a Phase 1 dose escalation study Sorafenib demonstrated a 50% response to stable disease on a 21 day schedule at a MTD of 400 mg twice daily [16]. Establishing the MTD proved Sorafenib’s action as a single agent and phase 2 trials in medullary thyroid cancer,renal cell carcinoma, prostate cancer and non-small cell lung cancer were investigated. Results were positive with upwards of 85% stable disease being noted. [17-23]. Sorafeniob in combination with docetaxel and cisplatin in patients suffering from gastric cancer was well tolerated and demonstrated improved efficacy [24], however, in combination with Capecitabine, Oxalaplatin and Ceuximab less encouraging results were observed [25]. In non-small cell lung cancer a combination of Erlotinib and Sorafenib demonstrate changed pharmacokinetics for Erlotinib indicating that these drug have a possible interaction but the combination did demostrate a positive outlook for EGFR mutation negative patients, suggesting also a possible biomarker for sensitivity. [26]

References

1. Jayanthan A, Bernoux D et al. Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition. Cancer Cell Int 2011; 11(1):44.

2. Kakodkar NC, Peddinti RR et al. Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth. Pediatr Blood Cancer 2011.

3. Procopio G, Verzoni E et al. Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial. Br J Cancer 2011; 104(8):1256-1261.

4. Wilhelm SM, Adnane L et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008; 7(10):3129-3140.

5. Tran MA, Smith CD et al. Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin Cancer Res 2008; 14(11):3571-3581.

6. Heo J, Breitbach CJ et al. Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy. Mol Ther 2011; 19(6):1170-1179.

7. Heim M, Scharifi M et al. The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines. Anticancer Drugs 2005; 16(2):129-136.

8. Activity of the Raf kinase inhibitor BAY 43-9006 in patients with advanced solid tumors. Clin Colorectal Cancer 2003; 3(1):16-18.

9. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002; 8(25):2255-2257.

10. Hilger RA, Kredke S et al. ERK1/2 phosphorylation: a biomarker analysis within a phase I study with the new Raf kinase inhibitor BAY43-9006. Int J Clin Pharmacol Ther 2002; 40(12):567-568.

11. Wilhelm SM, Carter C et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64(19):7099-7109.

12. Heim M, Sharifi M et al. Antitumor effect and potentiation or reduction in cytotoxic drug activity in human colon carcinoma cells by the Raf kinase inhibitor (RKI) BAY 43-9006. Int J Clin Pharmacol Ther 2003; 41(12):616-617.

13. Strumberg D, Voliotis D et al. Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors. Int J Clin Pharmacol Ther 2002; 40(12):580-581.

14. Mross K, Steinbild S et al. Drug-drug interaction pharmacokinetic study with the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with irinotecan (CPT-11) in patients with solid tumors. Int J Clin Pharmacol Ther 2003; 41(12):618-619.

15. Richly H, Kupsch P et al. A phase I clinical and pharmacokinetic study of the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with doxorubicin in patients with solid tumors. Int J Clin Pharmacol Ther 2003; 41(12):620-621.

16. Moore M, Hirte HW et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 2005; 16(10):1688-1694.

17. Abou-Alfa GK, Schwartz L et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24(26):4293-4300.

18. Eisen T, Ahmad T et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer 2006; 95(5):581-586.

19. Ratain MJ, Eisen T et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24(16):2505-2512.

20. Akaza H, Tsukamoto T et al. Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma. Jpn J Clin Oncol 2007; 37(10):755-762.

21. Elser C, Siu LL et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007; 25(24):3766-3773.

22. Gollob JA, Rathmell WK et al. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 2007; 25(22):3288-3295.

23. Gridelli C, Rossi A et al. A randomized phase II study of sorafenib/gemcitabine or sorafenib/erlotinib for advanced non-small-cell lung cancer in elderly patients or patients with a performance status of 2: treatment rationale and protocol dynamics. Clin Lung Cancer 2007; 8(6):396-398.

24. Sun W, Powell M et al. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 2010; 28(18):2947-2951.

25. Sanoff HK, Bernard S et al. Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab for Advanced Hepatocellular Carcinoma. Gastrointest Cancer Res 2011; 4(3):78-83.

26. Lind JS, Dingemans AM et al. A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer. Clin Cancer Res 2010; 16(11):3078-3087.