Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

A Corrigendum to this article was published on 01 February 2007

Key Points

  • Increased understanding of the molecular basis of cancer since the 1980s has shifted the focus of drug discovery and development away from non-specific chemotherapeutics and towards rationally designed drugs that target cancer-specific pathways.

  • The Raf serine/threonine kinase isoforms (A-Raf, B-Raf and Raf1(or C-Raf)) are the first kinases in the MAPK cascade and are pivotal regulators of cellular proliferation and survival.

  • In 1989, it was shown that disrupting the raf1 gene using the specific antisense oligonucleotide (ASON) ISIS 5132 inhibits the growth of human lung, breast and ovarian tumour xenografts in athymic mice, providing the first proof-of-concept that the raf1 gene is a valid anticancer target.

  • By 1994, Bayer and Onyx had engaged in a collaboration to discover novel therapies targeting the RAS–RAF–MEK–ERK pathway. HTS screening for Raf1 kinase inhibitory activity was initiated in 1995, and identified a promising lead compound that was subsequently optimized by medicinal chemistry efforts to give sorafenib.

  • Sorafenib directly blocks the autophosphorylation of several receptor tyrosine kinases (RTKs) —VEGFR1, 2 and3, PDGFRβ, c-Kit and RET — as well as inhibiting downstream Raf kinase isoforms in cell lines. The targeting of several RTKs involved in angiogenesis (VEGFR1, 2, 3 and PDGFRβ) and tumorigenesis (Flt-3, c-Kit and RET) might be responsible for its broad-spectrum activity in several models of human cancer.

  • As the molecular targets of sorafenib are involved in the aetiology of many common malignancies, it was first evaluated in a mixed population of patients with several forms of advanced solid tumours.

  • On the basis of the promising preliminary activity in renal cell carcinoma (RCC) patients across the Phase I trials, Bayer and Onyx decided to evaluate sorafenib monotherapy as a treatment for RCC by enriching the recruitment of RCC in an accruing Phase II trial, with a randomized discontinuation trial design.

  • The very high rate of RCC patients who were progression-free after 12 weeks of dosing in this Phase II trial led to the initiation of the Phase III study to assess the safety and activity of sorafenib.

  • These two randomized controlled trials confirmed sorafenib's activity against RCC by showing that it significantly prolonged progression-free survival (PFS) compared with placebo in patients with advanced disease

  • The Phase II/III results established oral sorafenib (400 mg bid) as a safe and effective new treatment for metastatic RCC and formed the basis for its FDA marketing approval in December 2005 for the treatment of advanced RCC.

  • Future issues for the development of sorafenib include the identification and validation of appropriate biomarkers for improved patient selection, prognostication and/or as response endpoints.

Abstract

Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) — from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 — was completed in just 11 years, with approval being received 5 years after the initiation of the first Phase I trial.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Summary of the chemical optimization of sorafenib.
Figure 2: Cellular targets of sorafenib.
Figure 3: Clinical activity of sorafenib in cancer efficacy trials.

Similar content being viewed by others

References

  1. Tabin, C. J. et al. Mechanism of activation of a human oncogene. Nature 300, 143–149 (1982).

    Article  CAS  PubMed  Google Scholar 

  2. Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297, 474–478 (1982).

    Article  CAS  PubMed  Google Scholar 

  3. Weinberg, R. A. Tumor suppressor genes. Science 254, 1138–1146 (1991).

    CAS  PubMed  Google Scholar 

  4. Gallo, R. C. & Wong-Staal, F. Retroviruses as etiologic agents of some animal and human leukemias and lymphomas and as tools for elucidating the molecular mechanism of leukemogenesis. Blood 60, 545–557 (1982).

    CAS  PubMed  Google Scholar 

  5. Varmus, H. Retroviruses. Science 240, 1427–1435 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Spector, D. H. et al. Uninfected avian cells contain RNA related to the transforming gene of avian sarcoma viruses. Cell 13, 371–379 (1978).

    Article  CAS  PubMed  Google Scholar 

  7. Bishop, J. M. Cellular oncogenes and retroviruses. Annu. Rev. Biochem. 52, 301–354 (1983).

    Article  CAS  PubMed  Google Scholar 

  8. Frost, P. & Kerbel, R. S. On a possible epigenetic mechanism(s) of tumor cell heterogeneity. The role of DNA methylation. Cancer Metastasis Rev. 2, 375–378 (1983).

    Article  CAS  PubMed  Google Scholar 

  9. Weinberg, R. A. The molecular basis of oncogenes and tumor suppressor genes. Ann. NY Acad. Sci. 758, 331–338 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Niman, H. L. Antisera to a synthetic peptide of the sis viral oncogene product recognize human platelet-derived growth factor. Nature 307, 180–183 (1984).

    Article  CAS  PubMed  Google Scholar 

  11. Coussens, L. et al. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature 320, 277–280 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. Schechter, A. L. et al. The neu oncogene: an erb-B-related gene encoding a 185, 000-Mr tumour antigen. Nature 312, 513–516 (1984).

    Article  CAS  PubMed  Google Scholar 

  13. Gill, G. N., Bertics, P. J. & Santon, J. B. Epidermal growth factor and its receptor. Mol. Cell Endocrinol. 51, 169–186 (1987).

    Article  CAS  PubMed  Google Scholar 

  14. Ishizawar, R. & Parsons, S. J. c-Src and cooperating partners in human cancer. Cancer Cell 6, 209–214 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Kranenburg, O. The KRAS oncogene: past, present, and future. Biochim. Biophys. Acta 1756, 81–82 (2005).

    CAS  PubMed  Google Scholar 

  16. Bos, J. L. Ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).

    CAS  PubMed  Google Scholar 

  17. Ponzielli, R., Katz, S., Barsyte-Lovejoy, D. & Penn, L. Z. Cancer therapeutics: targeting the dark side of Myc. Eur. J. Cancer 41, 2485–2501 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Milde-Langosch, K. The Fos family of transcription factors and their role in tumourigenesis. Eur. J. Cancer 41, 2449–2461 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Weiss, C. & Bohmann, D. Deregulated repression of c-Jun provides a potential link to its role in tumorigenesis. Cell Cycle 3, 111–113 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Kolch, W., Kotwaliwale, A., Vass, K. & Janosch, P. The role of Raf kinases in malignant transformation. Expert. Rev. Mol. Med. 2002, 1–18 (2002). Review on the importance of Raf kinase signalling in tumour cells.

    Google Scholar 

  21. O'Neill, E., Rushworth, L., Baccarini, M. & Kolch, W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306, 2267–2270 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Brose, M. S. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002).

    CAS  PubMed  Google Scholar 

  23. Salvatore, G. et al. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 89, 5175–5180 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Melillo, R. M. et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J. Clin. Invest. 115, 1068–1081 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nature Rev. Cancer 3, 11–22 (2003).

    Article  CAS  Google Scholar 

  26. Oka, H. et al. Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res. 55, 4182–4187 (1995).

    CAS  PubMed  Google Scholar 

  27. Hwang, Y. H. et al. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol. Res. 29, 113–121 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. McPhillips, F. et al. Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. Br. J. Cancer 85, 1753–1758 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mukherjee, R., Bartlett, J. M., Krishna, N. S., Underwood, M. A. & Edwards, J. Raf-1 expression may influence progression to androgen insensitive prostate cancer. Prostate 64, 101–107 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Kasid, U. & Dritschilo, A. RAF antisense oligonucleotide as a tumor radiosensitizer. Oncogene 22, 5876–5884 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Lyons, J. F., Wilhelm, S., Hibner, B. & Bollag, G. Discovery of a novel Raf kinase inhibitor. Endocrine-Related Cancer 8, 219–225 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. McDonald, O. B. et al. A scintillation proximity assay for the Raf/MEK/ERK kinase cascade: high-throughput screening and identification of selective enzyme inhibitors. Anal. Biochem. 268, 318–329 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493–502 (2002).

    Article  CAS  Google Scholar 

  34. Dowell, J., Minna, J. D. & Kirkpatrick, P. Erlotinib hydrochloride. Nature Rev. Drug Discov. 4, 13–14 (2005).

    Article  CAS  Google Scholar 

  35. Zhang, Z. et al. Oncogenes as novel targets for cancer therapy (part I): growth factors and protein tyrosine kinases. Am. J. Pharmacogenomics 5, 173–190 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Aherne, G. W., McDonald, E. & Workman, P. Finding the needle in the haystack: why high-throughput screening is good for your health. Breast Cancer Res. 4, 148–154 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Riedl, B. et al. Potent Raf kinase inhibitors from the diphenylurea class: structure activity relationships. Clin. Cancer Res. 20, 83a (2001).

    Google Scholar 

  39. Smith, R. A. et al. Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach. Bioorg. Med. Chem. Lett. 11, 2775–2778 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Lowinger, T. B., Riedl, B., Dumas, J. & Smith, R. A. Design and discovery of small molecules targeting raf-1 kinase. Curr. Pharm. Des. 8, 2269–2278 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Wilhelm, S. et al. BAY 43-9006, a novel Raf-1 kinase inhibitor (RKI) blocks the Raf/MEK/ERK pathway in tumor cells. Proc. Am. Assoc. Cancer Res. 42, 923 (2001).

    Google Scholar 

  42. Wilhelm, S. M. et al. BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the Raf/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004). Preclinical data describing sorafenib pharmacological target profile and effects on MAPK signalling and anti-angiogenic activity in preclinical human tumour xenograft models in rodents.

    Article  CAS  PubMed  Google Scholar 

  43. Carlomagno, F. et al. BAY 43-9006 inhibition of oncogenic RET mutants. J. Natl. Cancer Inst. 98, 326–334 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004). Pivotal paper describing how sorafenib induces inhibition of Raf1, wild-type B-Raf and b-raf V600E , by binding to and stabilizing the conserved kinase domain. This paper confirmed the SAR observations.

    Article  CAS  PubMed  Google Scholar 

  45. Nagar, B. et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 62, 4236–4243 (2002).

    CAS  PubMed  Google Scholar 

  46. Sharma, A. et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 65, 2412–2421 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Chang, Y. S. et al. BAY 43-9006 (Sorafenib) inhibits ectopic and orthotopic growth of a murine model of renal adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis. Clin. Cancer Res. 46, 5831 (2005).

    Google Scholar 

  48. Liu, L. et al. Sorafenib (BAY 43-9006) inhibits the Raf/MEK/ERK pathway in hepatocellular carcinoma (HCC) cells and produces robust efficacy against PLC/PRF/5 HCC tumors in mice. Poster presentation Am. Assoc. Cancer Res.–Natl Cancer Inst.–Eur. Organiz. Res. Treat. Cancer. Philadelphia, Pennsylvania (2005).

    Google Scholar 

  49. Yu, C. et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 24, 6861–6869 (2005). Preclinical data describing the downregulation of the prosurvival protein MCL1 and pro-apoptotic activity of sorafenib in tumour cells.

    Article  CAS  PubMed  Google Scholar 

  50. Rahmani, M., Maynard Davis, E., Bauer, C., Dent, P. & Grant, S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of mcl-1 through inhibition of translation. J. Biol. Chem. 280, 35217–35227 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Panka, D. J., Wang, W., Atkins, M. B. & Mier, J. W. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 66, 1611–1619 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Strumberg, D. et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J. Clin. Oncol. 23, 965–972 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Clark, J. W., Eder, J. P., Ryan, D., Lee, R. & Lenz, H.-J. The safety and pharmacokinetics of the multi-targeted tyrosine kinase inhibitor (including Raf kinase and VEGF kinase), BAY 43-9006, in patients with advanced, refractory solid tumors. Clin. Cancer Res. 11, 5472–5480 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Awada, A. et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br. J. Cancer 92, 1855–1861 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Moore, M. 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. 16, 1688–1694 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Strumberg, D. et al. Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? Eur. J. Cancer 42, 548–556 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Kupsch, P. et al. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin. Colorectal Cancer 5, 188–196 (2005).

    Article  PubMed  Google Scholar 

  58. Figer, A. et al. Phase I trial of BAY 43-9006 in combination with 5-fluorouracil (5-FU) and leucovorin (LCV) in patients with advanced refractory solid tumors. Ann. Oncol. 15, iii87 (2004).

  59. Flaherty, K. T. et al. Sorafenib combined with carboplatin and paclitaxel for metastatic melanoma: PFS and response versus B-Raf status. Proc. 4th Intl. Symp. Targeted Anticancer Ther. Amsterdam, The Netherlands [online], (2006).

    Google Scholar 

  60. Siu, L. L. et al. Phase I/II trial of sorafenib and gemcitabine in advanced solid tumors and in advanced pancreatic cancer. Clin. Cancer Res. 12, 144–151 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Richly, H. et al. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann. Oncol. 17, 866–873 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Awada, A. et al. A Phase I study of BAY 43-9006, a novel Raf kinase and VEGFR inhibitor, in combination with Taxotere in patients with advanced solid tumors. Poster presentation Am. Assoc. Cancer Res.–Natl Cancer Inst.–Eur. Organiz. Res. Treat. Cancer. Geneva, Switzerland (2004).

    Google Scholar 

  63. Steinbild, S. et al. Phase I study of BAY 43-9006 (sorafenib), a Raf kinase and VEGFR inhibitor, combined with irinotecan (CPT-11) in advanced solid tumors. J. Clin. Oncol. 23, 3115 (2005).

    Article  Google Scholar 

  64. Eisen, T. et al. Phase I trial of BAY 43-9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients. J. Clin. Oncol. 23, 7508 (2005).

    Article  Google Scholar 

  65. Gollob, J. et al. Phase II trial of sorafenib (BAY 43-9006) in combination with interferon alpha 2b in patients with metastatic renal cell carcinoma. Eur. J. Cancer Supplements 3, 226 (2005).

    Google Scholar 

  66. Robert, C. et al. Phase I trial of sorafenib (BAY 43-9006) in combination with interferon alpha 2a in patients with unresectable and/or metastatic renal cell carcinoma and malignant melanoma. Eur. J. Cancer Supplements 3, 254 (2005).

    Google Scholar 

  67. Hainsworth, J. D. et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J. Clin. Oncol. 23, 7889–7896 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Takahashi, A. et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 54, 4233–4237 (1994).

    CAS  PubMed  Google Scholar 

  69. Smith, K. et al. Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer. Cancer Res. 65, 5221–5230 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Gunaratnam, L. et al. Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J. Biol. Chem. 278, 44966–44974 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Ratain, M. J. et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 2505–2512 (2006). Pivotal Phase II trial demonstrating sorafenib's significant PFS benefit over placebo and its acceptable tolerability in patients with advanced refractory RCC. These findings formed the basis of sorafenib's recent FDA approval for this indication.

    Article  CAS  PubMed  Google Scholar 

  72. Escudier, B. et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Eur. J. Cancer Supplements 3, 226 (2005). Pivotal Phase III trial confirming sorafenib's significant PFS benefit and acceptable tolerability in patients with advanced refractory RCC. These findings formed the basis of sorafenib's recent FDA approval for this indication.

    Google Scholar 

  73. Motzer, R. J. et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J. Clin. Oncol. 22, 454–463 (2004).

    Article  PubMed  Google Scholar 

  74. Abou-Alfa, G. K. et al. Phase II biomarker analysis of sorafenib (BAY 43-9006) in patients with advanced hepatocellular carcinoma. Poster presentation Am. Assoc. Cancer Res.–Natl Cancer Inst.–Eur. Organiz. Res. Treat. Cancer. Philadelphia, Pennsylvania (2005).

    Google Scholar 

  75. Gatzemeier, U. et al. Phase II trial of single-agent sorafenib in patients with advanced non-small-cell lung carcinoma. J. Clin. Oncol. 24, 364s (2006).

    Google Scholar 

  76. Kloos, R. et al. Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43-9006 in patients with metastatic papillary thyroid carcinoma (PTC): Updated results of a phase II study. J. Clin. Oncol. 24, 288s (2006).

    Article  CAS  Google Scholar 

  77. Steinbild, S. et al. Phase II study of sorafenib (BAY43-9006) in hormone-refractory patients with prostate cancer: a study of the Central European Society for Anticancer Drug Research — EWIV (CESAR). J. Clin. Oncol. 24, 144s (2006).

    Google Scholar 

  78. Dahut, W. L. et al. Bony metastatic disease responses to sorafenib (BAY 43-9006) independent of PSA in patients with metastatic androgen independent prostate cancer. J. Clin. Oncol. 24, 218s (2006).

    Google Scholar 

  79. Moreno-Aspitia, A. et al. BAY 43-9006 as single oral agent in patients with metastatic breast cancer previously exposed to anthracycline and/or taxane. J. Clin. Oncol. 24, 577 (2006).

    Google Scholar 

  80. Wright, J. J., Zerivitz, K. & Gravell, A. Clinical trials referral resource. Current clinical trials of BAY 43-9006, Part 1. Oncology (Williston Park) 19, 499–502 (2005).

    Google Scholar 

  81. Lorigan, P. et al. Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients. J. Clin. Oncol. 24, 8012 (2006).

    Google Scholar 

  82. Sosman, J. et al. A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts). J. Clin. Oncol. 24, 128s (2006).

    Google Scholar 

  83. Azad, N. S. et al. Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab. J. Clin. Oncol. 24, 121s (2006).

    Google Scholar 

  84. Elting, J. et al. Biomarkers associated with clinical outcomes in TARGETs, a Phase III single-agent, placebo-controlled study of sorafenib in advanced renal cell carcinoma. Proc. Am. Assoc. Cancer Res. 47, A2909 (2006).

    Google Scholar 

  85. Advani, A. S. C-kit as a target in the treatment of acute myelogenous leukemia. Curr. Hematol. Rep. 4, 51–58 (2005).

    CAS  PubMed  Google Scholar 

  86. Markovic, A., MacKenzie, K. L. & Lock, R. B. FLT-3: a new focus in the understanding of acute leukemia. Int. J. Biochem. Cell Biol. 37, 1168–1172 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Chen, L. L. et al. Imatinib resistance in gastrointestinal stromal tumors. Curr. Oncol. Rep. 7, 293–299 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Kodama, Y. et al. The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. Cancer Sci. 96, 143–148 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Flaherty, K. T. et al. Phase I/II, pharmacokinetic and pharmacodynamic trial of BAY 43-9006 alone in patients with metastatic melanoma. Proc. Am. Soc. Clin. Oncol. 23, 201s (2005).

    Google Scholar 

  90. Blumenschein, G. R. et al. Phase II multicenter uncontrolled trial of single agent sorafenib (BAY 43-9006) in relapsed or refractory advanced non-small cell lung cancer. Poster presentation Am. Assoc. Cancer Res.–Natl Cancer Inst.–Eur. Organiz. Res. Treat. Cancer. Philadelphia, Pennsylvania (2005).

    Google Scholar 

  91. Salvatore, G. et al. B-RAF is a therapeutic target in aggressive thyroid carcinoma. Clin. Cancer Res. 12, 1623–1629 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Levy, J. et al. Analysis of transcription and protein expression changes in the 786-O human renal cell carcinoma tumor xenograft model in response to treatment with the multi-kinase inhibitor sorafenib (BAY 43-9006). Proc. Am. Assoc. Cancer Res. 47, 213–214 (2006).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Scott Wilhelm.

Ethics declarations

Competing interests

The authors work for Bayer HealthCare Pharmacueticals and own stock in Bayer Pharma.

Related links

Related links

FURTHER INFORMATION

Nexavar

Glossary

Metastasis

The spread of cancer cells through lymphatics/blood vessels to other sites or tissues in the body (for example, brain or liver).

Epigenetic events

Reversible heritable changes in gene function or other cell phenotype that occur without a change in DNA sequence.

Therapeutic Index

(Also known as therapeutic ratio or margin of safety). A comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects.

Scintillation proximity assay (SPA)

A process that uses fluoromicrospheres coated with streptavidin to detect phosphorylation of substrates by kinases, which has become an important technique in high-throughput screening (HTS) for new drugs.

Xenograft

Xenograft mouse models of cancer are created by injecting homogeneous human tumour cell lines into immunodeficient mice.

Combinatorial chemistry

Any of various technologies for the rapid synthesis of large collections of compounds to facilitate the identification of new active compounds for drug targets by high-throughput screening techniques.

IC50

The half maximal inhibitory concentration, or the concentration of an inhibitor that is required for 50% inhibition of a biochemical or cellular target.

Angiogenesis

The growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development but is also a fundamental process required for the growth of tumours.

Pericytes

Elongated contractile cells found in association with arterioles outside the basement membrane.

Apoptosis

Programmed cell death.

RECIST criteria

Response Evaluation Criteria in Solid Tumors are standardized, radiographic criteria for determining tumour response or progression in clinical trials of cancer drugs.

Randomized discontinuation trial (RDT) design

A two-phase trial: in Phase I all patients are openly treated with the medication being evaluated; in Phase II, those with stable disease are randomly assigned to continue the same treatment or switch to placebo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilhelm, S., Carter, C., Lynch, M. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5, 835–844 (2006). https://doi.org/10.1038/nrd2130

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2130

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing