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Chemical Compound Review

Nexavar     4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]...

Synonyms: Sorafenib, sorafenibum, QCR-65, SORAFENIB BASE, CHEMBL1336, ...
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Disease relevance of Sorafenib


High impact information on Sorafenib


Chemical compound and disease context of Sorafenib


Biological context of Sorafenib


Anatomical context of Sorafenib

  • Here we report that treatment with BAY 43-9006 results in marked cytochrome c and AIF release into the cytosol, caspase-9, -8, -7, and -3 activation, and apoptosis in human leukemia cells (U937, Jurkat, and K562) [18].
  • These effects were mimicked by thyroid carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 micromol/L; P < 0.0001), whereas the compound had negligible effects in normal thyrocytes [19].
  • In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a K(i) value of 2.7 mumol/l. CONCLUSION: Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m(2) or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended [20].
  • METHODS: The previously described whole blood lysis method was used to monitor BAY 43-9006 effects on peripheral T-cells of solid tumor patients [21].
  • METHODS: We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific antibodies [22].

Associations of Sorafenib with other chemical compounds

  • Sorafenib decreased mRNA levels of TNFalpha, VEGF receptor 2, VEGF receptor 1, transforming growth factor beta, cyclooxygenase 1, and expression of various genes that are involved in pathways of cellular proliferation, fibrogenesis, tissue remodeling, inflammation, and angiogenesis [23].
  • Sorafenib blocks signaling and synergizes with rapamycin in vivo, preventing tumor progression [24].
  • Tanespimycin did not alter sorafenib concentrations [25].
  • Pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC [26].
  • Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients [27].
  • UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure [28].
  • Sorafenib combined with gefitinib significantly inhibited tumor growth in mice and reduced cell viability in vitro compared to single agents [29].
  • We have identified several factors affecting interpatient variability in sorafenib metabolism to the active N-oxide metabolite including age, sex, and concurrent treatment with azole antifungals [30].
  • The recommended phase II doses are sorafenib, 90 mg/m(2) twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m(2) once daily [31].
  • Whereas Oatp1b2 deficiency in vivo had minimal influence on parent and active metabolite N-oxide drug exposure, plasma levels of the glucuronic acid metabolite of sorafenib (sorafenib-glucuronide) were increased more than 8-fold in Oatp1b2-knockout mice [32].
  • Two patients did not respond to sorafenib combination therapy or sunitinib [33].

Gene context of Sorafenib


Analytical, diagnostic and therapeutic context of Sorafenib


  1. Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant. Lierman, E., Folens, C., Stover, E.H., Mentens, N., Van Miegroet, H., Scheers, W., Boogaerts, M., Vandenberghe, P., Marynen, P., Cools, J. Blood (2006) [Pubmed]
  2. 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. Strumberg, D., Richly, H., Hilger, R.A., Schleucher, N., Korfee, S., Tewes, M., Faghih, M., Brendel, E., Voliotis, D., Haase, C.G., Schwartz, B., Awada, A., Voigtmann, R., Scheulen, M.E., Seeber, S. J. Clin. Oncol. (2005) [Pubmed]
  3. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Panka, D.J., Wang, W., Atkins, M.B., Mier, J.W. Cancer Res. (2006) [Pubmed]
  4. 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. Wilhelm, S.M., Carter, C., Tang, L., Wilkie, D., McNabola, A., Rong, H., Chen, C., Zhang, X., Vincent, P., McHugh, M., Cao, Y., Shujath, J., Gawlak, S., Eveleigh, D., Rowley, B., Liu, L., Adnane, L., Lynch, M., Auclair, D., Taylor, I., Gedrich, R., Voznesensky, A., Riedl, B., Post, L.E., Bollag, G., Trail, P.A. Cancer Res. (2004) [Pubmed]
  5. Targeting Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase in the Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases. Sharma, A., Tran, M.A., Liang, S., Sharma, A.K., Amin, S., Smith, C.D., Dong, C., Robertson, G.P. Cancer Res. (2006) [Pubmed]
  6. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. Wang, Y., Gao, J., Zhang, D., Zhang, J., Ma, J., Jiang, H. J. Hepatol. (2010) [Pubmed]
  7. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. Park, J.W., Koh, Y.H., Kim, H.B., Kim, H.Y., An, S., Choi, J.I., Woo, S.M., Nam, B.H. J. Hepatol. (2012) [Pubmed]
  8. Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial. Tabernero, J., Garcia-Carbonero, R., Cassidy, J., Sobrero, A., Van Cutsem, E., Köhne, C.H., Tejpar, S., Gladkov, O., Davidenko, I., Salazar, R., Vladimirova, L., Cheporov, S., Burdaeva, O., Rivera, F., Samuel, L., Bulavina, I., Potter, V., Chang, Y.L., Lokker, N.A., O'Dwyer, P.J. Clin. Cancer Res. (2013) [Pubmed]
  9. Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. Galanis, E., Anderson, S.K., Lafky, J.M., Uhm, J.H., Giannini, C., Kumar, S.K., Kimlinger, T.K., Northfelt, D.W., Flynn, P.J., Jaeckle, K.A., Kaufmann, T.J., Buckner, J.C. Clin. Cancer Res. (2013) [Pubmed]
  10. Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates. Meyer, J.M., Perlewitz, K.S., Hayden, J.B., Doung, Y.C., Hung, A.Y., Vetto, J.T., Pommier, R.F., Mansoor, A., Beckett, B.R., Tudorica, A., Mori, M., Holtorf, M.L., Afzal, A., Woodward, W.J., Rodler, E.T., Jones, R.L., Huang, W., Ryan, C.W. Clin. Cancer Res. (2013) [Pubmed]
  11. Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo. Chen, C.H., Chen, M.C., Wang, J.C., Tsai, A.C., Chen, C.S., Liou, J.P., Pan, S.L., Teng, C.M. Clin. Cancer Res. (2014) [Pubmed]
  12. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Liu, L., Cao, Y., Chen, C., Zhang, X., McNabola, A., Wilkie, D., Wilhelm, S., Lynch, M., Carter, C. Cancer Res. (2006) [Pubmed]
  13. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Siu, L.L., Awada, A., Takimoto, C.H., Piccart, M., Schwartz, B., Giannaris, T., Lathia, C., Petrenciuc, O., Moore, M.J. Clin. Cancer Res. (2006) [Pubmed]
  14. Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. Jane, E.P., Premkumar, D.R., Pollack, I.F. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  15. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Richly, H., Henning, B.F., Kupsch, P., Passarge, K., Grubert, M., Hilger, R.A., Christensen, O., Brendel, E., Schwartz, B., Ludwig, M., Flashar, C., Voigtmann, R., Scheulen, M.E., Seeber, S., Strumberg, D. Ann. Oncol. (2006) [Pubmed]
  16. Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma. Carter, C.A., Chen, C., Brink, C., Vincent, P., Maxuitenko, Y.Y., Gilbert, K.S., Waud, W.R., Zhang, X. Cancer Chemother. Pharmacol. (2007) [Pubmed]
  17. Does the Expression of c-kit (CD117) in Neuroendocrine Tumors Represent a Target for Therapy? Koch, C.A., Gimm, O., Vortmeyer, A.O., Al-Ali, H.K., Lamesch, P., Ott, R., Kluge, R., Bierbach, U., Tannapfel, A. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
  18. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. Rahmani, M., Davis, E.M., Bauer, C., Dent, P., Grant, S. J. Biol. Chem. (2005) [Pubmed]
  19. BRAF is a therapeutic target in aggressive thyroid carcinoma. Salvatore, G., De Falco, V., Salerno, P., Nappi, T.C., Pepe, S., Troncone, G., Carlomagno, F., Melillo, R.M., Wilhelm, S.M., Santoro, M. Clin. Cancer Res. (2006) [Pubmed]
  20. Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. Mross, K., Steinbild, S., Baas, F., Gmehling, D., Radtke, M., Voliotis, D., Brendel, E., Christensen, O., Unger, C. Eur. J. Cancer (2007) [Pubmed]
  21. Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells. Tong, F.K., Chow, S., Hedley, D. Cytometry. Part B, Clinical cytometry. (2006) [Pubmed]
  22. BAY 43-9006 inhibition of oncogenic RET mutants. Carlomagno, F., Anaganti, S., Guida, T., Salvatore, G., Troncone, G., Wilhelm, S.M., Santoro, M. J. Natl. Cancer Inst. (2006) [Pubmed]
  23. Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. Reiberger, T., Angermayr, B., Schwabl, P., Rohr-Udilova, N., Mitterhauser, M., Gangl, A., Peck-Radosavljevic, M. J. Hepatol. (2009) [Pubmed]
  24. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. Newell, P., Toffanin, S., Villanueva, A., Chiang, D.Y., Minguez, B., Cabellos, L., Savic, R., Hoshida, Y., Lim, K.H., Melgar-Lesmes, P., Yea, S., Peix, J., Deniz, K., Fiel, M.I., Thung, S., Alsinet, C., Tovar, V., Mazzaferro, V., Bruix, J., Roayaie, S., Schwartz, M., Friedman, S.L., Llovet, J.M. J. Hepatol. (2009) [Pubmed]
  25. Safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of sorafenib and tanespimycin. Vaishampayan, U.N., Burger, A.M., Sausville, E.A., Heilbrun, L.K., Li, J., Horiba, M.N., Egorin, M.J., Ivy, P., Pacey, S., Lorusso, P.M. Clin. Cancer Res. (2010) [Pubmed]
  26. AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). Huynh, H., Ngo, V.C., Koong, H.N., Poon, D., Choo, S.P., Toh, H.C., Thng, C.H., Chow, P., Ong, H.S., Chung, A., Goh, B.C., Smith, P.D., Soo, K.C. J. Hepatol. (2010) [Pubmed]
  27. Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. Hsu, C.H., Shen, Y.C., Lin, Z.Z., Chen, P.J., Shao, Y.Y., Ding, Y.H., Hsu, C., Cheng, A.L. J. Hepatol. (2010) [Pubmed]
  28. Sorafenib Is an Inhibitor of UGT1A1 but Is Metabolized by UGT1A9: Implications of Genetic Variants on Pharmacokinetics and Hyperbilirubinemia. Peer, C.J., Sissung, T.M., Kim, A., Jain, L., Woo, S., Gardner, E.R., Kirkland, C.T., Troutman, S.M., English, B.C., Richardson, E.D., Federspiel, J., Venzon, D., Dahut, W., Kohn, E., Kummar, S., Yarchoan, R., Giaccone, G., Widemann, B., Figg, W.D. Clin. Cancer Res. (2012) [Pubmed]
  29. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. Blivet-Van Eggelpoël, M.J., Chettouh, H., Fartoux, L., Aoudjehane, L., Barbu, V., Rey, C., Priam, S., Housset, C., Rosmorduc, O., Desbois-Mouthon, C. J. Hepatol. (2012) [Pubmed]
  30. Ontogeny and sorafenib metabolism. Zimmerman, E.I., Roberts, J.L., Li, L., Finkelstein, D., Gibson, A., Chaudhry, A.S., Schuetz, E.G., Rubnitz, J.E., Inaba, H., Baker, S.D. Clin. Cancer Res. (2012) [Pubmed]
  31. Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. Navid, F., Baker, S.D., McCarville, M.B., Stewart, C.F., Billups, C.A., Wu, J., Davidoff, A.M., Spunt, S.L., Furman, W.L., McGregor, L.M., Hu, S., Panetta, J.C., Turner, D., Fofana, D., Reddick, W.E., Leung, W., Santana, V.M. Clin. Cancer Res. (2013) [Pubmed]
  32. Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Zimmerman, E.I., Hu, S., Roberts, J.L., Gibson, A.A., Orwick, S.J., Li, L., Sparreboom, A., Baker, S.D. Clin. Cancer Res. (2013) [Pubmed]
  33. Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Baker, S.D., Zimmerman, E.I., Wang, Y.D., Orwick, S., Zatechka, D.S., Buaboonnam, J., Neale, G.A., Olsen, S.R., Enemark, E.J., Shurtleff, S., Rubnitz, J.E., Mullighan, C.G., Inaba, H. Clin. Cancer Res. (2013) [Pubmed]
  34. Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement. Henderson, Y.C., Ahn, S.H., Kang, Y., Clayman, G.L. Clin. Cancer Res. (2008) [Pubmed]
  35. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Liu, L.P., Ho, R.L., Chen, G.G., Lai, P.B. Clin. Cancer Res. (2012) [Pubmed]
  36. Targeting von hippel-lindau pathway in renal cell carcinoma. Patel, P.H., Chadalavada, R.S., Chaganti, R.S., Motzer, R.J. Clin. Cancer Res. (2006) [Pubmed]
  37. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Ahmad, T., Eisen, T. Clin. Cancer Res. (2004) [Pubmed]
  38. Improving outcomes in advanced malignant melanoma: update on systemic therapy. Danson, S., Lorigan, P. Drugs (2005) [Pubmed]
  39. Design and discovery of small molecules targeting raf-1 kinase. Lowinger, T.B., Riedl, B., Dumas, J., Smith, R.A. Curr. Pharm. Des. (2002) [Pubmed]
  40. Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? Strumberg, D., Awada, A., Hirte, H., Clark, J.W., Seeber, S., Piccart, P., Hofstra, E., Voliotis, D., Christensen, O., Brueckner, A., Schwartz, B. Eur. J. Cancer (2006) [Pubmed]
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