Archives of Pharmacal Research

, Volume 35, Issue 4, pp 605–615 | Cite as

Novel small molecule Raf kinase inhibitors for targeted cancer therapeutics

  • Do-Hee Kim
  • Taebo SimEmail author


Aberrant activation of Raf signaling pathway is frequently found in various human tumors, it has been considered as distinct and promising molecular target for cancer therapeutics. B-Raf is most attractive drug target out of three Raf isoforms (A-Raf, B-Raf and C-Raf) because it exhibits high kinase activity due to frequent mutations in human tumors. However, most recently, it has been reported that Raf isoforms show the cross-activation in the presence of specific B-Raf inhibitors, which brings about the paradoxical p-ERK activation as well as tumor promoting effect. According to these findings, it remains controversy whether pan-Raf kinase inhibitor is more valuable and promising rather than specific B-Raf inhibitor under certain conditions in terms of cancer therapeutics. In this short review, novel Raf kinase inhibitors undergoing clinical investigation are introduced. Moreover, the paradoxical p-ERK activation is discussed with specific B-Raf inhibitors, PLX4032/4720 compounds.

Key words

Raf kinase Molecular-targeted inhibitor Cancer Sorafenib PLX4720/4032 


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  1. Ahmad, T. and Eisen, T., Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin. Cancer Res., 10, 6388S–6392S (2004).PubMedCrossRefGoogle Scholar
  2. Ahnstedt, H., Saveland, H., Nilsson, O., and Edvinsson, L., Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway. BMC Neurosci., 12, 5 (2011).PubMedCrossRefGoogle Scholar
  3. Amiri, P., Aikawa, M. E., Dove, J., Stuart, D. D., Poon, D., Pick, T., Ramurthy, S., Subramanian, S., Levine, B., Costales, A., Harris, A., and Paul, R., CHIR-265 is a potent selective inhibitor of c-Raf/B-Raf/mutB-Raf that effectively inhibits proliferation and survival of cancer cell lines with Ras/Raf pathway mutations. AACR Meeting Abstracts, 2006, 1140a (2006).Google Scholar
  4. Auclair, D., Miller, D., Yatsula, V., Pickett, W., Carter, C., Chang, Y., Zhang, X., Wilkie, D., Burd, A., Shi, H., Rocks, S., Gedrich, R., Abriola, L., Vasavada, H., Lynch, M., Dumas, J., Trail, P. A., and Wilhelm, S. M., Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia, 21, 439–445 (2007).PubMedCrossRefGoogle Scholar
  5. Bollag, G., Hirth, P., Tsai, J., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W., Zhang, C., Zhang, Y., Habets, G., Burton, E. A., Wong, B., Tsang, G., West, B. L., Powell, B., Shellooe, R., Marimuthu, A., Nguyen, H., Zhang, K. Y., Artis, D. R., Schlessinger, J., Su, F., Higgins, B., Iyer, R., D’andrea, K., Koehler, A., Stumm, M., Lin, P. S., Lee, R. J., Grippo, J., Puzanov, I., Kim, K. B., Ribas, A., Mcarthur, G. A., Sosman, J. A., Chapman, P. B., Flaherty, K. T., Xu, X., Nathanson, K. L., and Nolop, K., Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 467, 596–599 (2010).PubMedCrossRefGoogle Scholar
  6. Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., Roth, J. A., Albelda, S. M., Davies, H., Cox, C., Brignell, G., Stephens, P., Futreal, P. A., Wooster, R., Stratton, M. R., and Weber, B. L., BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res., 62, 6997–7000 (2002).PubMedGoogle Scholar
  7. Burger, R. A., Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol. Oncol., 121, 230–238 (2011).PubMedCrossRefGoogle Scholar
  8. Chang, Y. S., Adnane, J., Trail, P. A., Levy, J., Henderson, A., Xue, D., Bortolon, E., Ichetovkin, M., Chen, C., Mcnabola, A., Wilkie, D., Carter, C. A., Taylor, I. C., Lynch, M., and Wilhelm, S., Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother. Pharmacol., 59, 561–674 (2007).PubMedCrossRefGoogle Scholar
  9. Cichowski, K. and Janne, P. A., Drug discovery: inhibitors that activate. Nature, 464, 358–359 (2010).PubMedCrossRefGoogle Scholar
  10. Corcoran, R. B., Dias-Santagata, D., Bergethon, K., Iafrate, A. J., Settleman, J., and Engelman, J. A., BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal., 3, ra84 (2010).PubMedCrossRefGoogle Scholar
  11. Dhomen, N. and Marais, R., BRAF signaling and targeted therapies in melanoma. Hematol. Oncol. Clin. North Am., 23, 529–545, ix (2009).PubMedCrossRefGoogle Scholar
  12. Dumas, J., Smith, R. A., and Lowinger, T. B., Recent developments in the discovery of protein kinase inhibitors from the urea class. Curr. Opin. Drug Discov. Devel., 7, 600–616 (2004).PubMedGoogle Scholar
  13. Eisen, T., Ahmad, T., Flaherty, K. T., Gore, M., Kaye, S., Marais, R., Gibbens, I., Hackett, S., James, M., Schuchter, L. M., Nathanson, K. L., Xia, C., Simantov, R., Schwartz, B., Poulin-Costello, M., O’dwyer, P. J., and Ratain, M. J., Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br. J. Cancer, 95, 581–586 (2006).PubMedCrossRefGoogle Scholar
  14. Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., Mcarthur, G. A., Sosman, J. A., O’dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., and Chapman, P. B., Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med., 363, 809–819 (2010).PubMedCrossRefGoogle Scholar
  15. Garnett, M. J. and Marais, R., Guilty as charged: B-RAF is a human oncogene. Cancer Cell, 6, 313–319 (2004).PubMedCrossRefGoogle Scholar
  16. Guida, T., Anaganti, S., Provitera, L., Gedrich, R., Sullivan, E., Wilhelm, S. M., Santoro, M., and Carlomagno, F., Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin. Cancer Res., 13, 3363–3369 (2007).PubMedCrossRefGoogle Scholar
  17. Halaban, R., Zhang, W., Bacchiocchi, A., Cheng, E., Parisi, F., Ariyan, S., Krauthammer, M., Mccusker, J. P., Kluger, Y., and Sznol, M., PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment. Cell Melanoma Res., 23, 190–200 (2010).PubMedCrossRefGoogle Scholar
  18. Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., Liu, B., Sideris, S., Hoeflich, K. P., Jaiswal, B. S., Seshagiri, S., Koeppen, H., Belvin, M., Friedman, L. S., and Malek, S., RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature, 464, 431–435 (2010).PubMedCrossRefGoogle Scholar
  19. Hauschild, A., Agarwala, S. S., Trefzer, U., Hogg, D., Robert, C., Hersey, P., Eggermont, A., Grabbe, S., Gonzalez, R., Gille, J., Peschel, C., Schadendorf, D., Garbe, C., O’day, S., Daud, A., White, J. M., Xia, C., Patel, K., Kirkwood, J. M., and Keilholz, U., Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol., 27, 2823–2830 (2009).PubMedCrossRefGoogle Scholar
  20. Heidorn, S. J., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C., and Marais, R., Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell, 140, 209–221 (2010).PubMedCrossRefGoogle Scholar
  21. Hoeflich, K. P., Herter, S., Tien, J., Wong, L., Berry, L., Chan, J., O’brien, C., Modrusan, Z., Seshagiri, S., Lackner, M., Stern, H., Choo, E., Murray, L., Friedman, L. S., and Belvin, M., Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res., 69, 3042–3051 (2009).PubMedCrossRefGoogle Scholar
  22. Huang, S. and Sinicrope, F. A., Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells. Mol. Cancer Ther., 9, 742–750 (2010).PubMedCrossRefGoogle Scholar
  23. Huynh, H., Lee, J. W., Chow, P. K., Ngo, V. C., Lew, G. B., Lam, I. W., Ong, H. S., Chung, A., Soo, K. C., Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. Mol. Cancer Ther., 8, 152–159 (2009)PubMedCrossRefGoogle Scholar
  24. Jiang, C. C., Lai, F., Thorne, R. F., Yang, F., Liu, H., Hersey, P., and Zhang, X. D., MEK-independent survival of BRAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin. Cancer Res., 17, 721–730 (2011).PubMedCrossRefGoogle Scholar
  25. Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., Caponigro, G., Hieronymus, H., Murray, R. R., Salehi-Ashtiani, K., Hill, D. E., Vidal, M., Zhao, J. J., Yang, X., Alkan, O., Kim, S., Harris, J. L., Wilson, C. J., Myer, V. E., Finan, P. M., Root, D. E., Roberts, T. M., Golub, T., Flaherty, K. T., Dummer, R., Weber, B. L., Sellers, W. R., Schlegel, R., Wargo, J. A., Hahn, W. C., and Garraway, L. A., COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 468, 968–972 (2010).PubMedCrossRefGoogle Scholar
  26. Joseph, E. W., Pratilas, C. A., Poulikakos, P. I., Tadi, M., Wang, W., Taylor, B. S., Halilovic, E., Persaud, Y., Xing, F., Viale, A., Tsai, J., Chapman, P. B., Bollag, G., Solit, D. B., and Rosen, N., The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc. Natl. Acad. Sci. U. S. A., 107, 14903–14908 (2010).PubMedCrossRefGoogle Scholar
  27. Kaplan, F. M., Shao, Y., Mayberry, M. M., and Aplin, A. E., Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene, 30, 366–371 (2011).PubMedCrossRefGoogle Scholar
  28. Karasarides, M., Chiloeches, A., Hayward, R., Niculescu-Duvaz, D., Scanlon, I., Friedlos, F., Ogilvie, L., Hedley, D., Martin, J., Marshall, C. J., Springer, C. J., and Marais, R., B-RAF is a therapeutic target in melanoma. Oncogene, 23, 6292–6298 (2004).PubMedCrossRefGoogle Scholar
  29. Kefford, R., Arkenau, H., Brown, M. P., Millward, M., Infante, J. R., Long, G. V., Ouellet, D., Curtis, M., Lebowitz, P. F., and Falchook, G. S., Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J. Clin. Oncol. 28, Abstract 8503 (2010).Google Scholar
  30. Khazak, V., Astsaturov, I., Serebriiskii, I. G., and Golemis, E. A., Selective Raf inhibition in cancer therapy. Expert Opin. Ther. Targets, 11, 1587–1609 (2007).PubMedCrossRefGoogle Scholar
  31. Kim, S., Yazici, Y. D., Calzada, G., Wang, Z. Y., Younes, M. N., Jasser, S. A., El-Naggar, A. K., and Myers, J. N., Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol. Cancer Ther., 6, 1785–1792 (2007).PubMedCrossRefGoogle Scholar
  32. King, A. J., Patrick, D. R., Batorsky, R. S., Ho, M. L., Do, H. T., Zhang, S. Y., Kumar, R., Rusnak, D. W., Takle, A. K., Wilson, D. M., Hugger, E., Wang, L., Karreth, F., Lougheed, J. C., Lee, J., Chau, D., Stout, T. J., May, E. W., Rominger, C. M., Schaber, M. D., Luo, L., Lakdawala, A. S., Adams, J. L., Contractor, R. G., Smalley, K. S., Herlyn, M., Morrissey, M. M., Tuveson, D. A., and Huang, P. S., Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res., 66, 11100–11105 (2006).PubMedCrossRefGoogle Scholar
  33. Kolch, W., Kotwaliwale, A., Vass, K., and Janosch, P., The role of Raf kinases in malignant transformation. Expert Rev. Mol. Med., 4, 1–18 (2002).PubMedCrossRefGoogle Scholar
  34. Lee, J. T. and Mccubrey, J. A., BAY-43-9006 Bayer/Onyx. Curr. Opin. Investig. Drugs, 4, 757–763 (2003).PubMedGoogle Scholar
  35. Liu, L., Cao, Y., Chen, C., Zhang, X., Mcnabola, A., Wilkie, D., Wilhelm, S., Lynch, M., and Carter, C., Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res., 66, 11851–11858 (2006).PubMedCrossRefGoogle Scholar
  36. Liu, Y. and Gray, N. S., Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol., 2, 358–364 (2006).PubMedCrossRefGoogle Scholar
  37. Lowinger, T. B., Riedl, B., Dumas, J., and Smith, R. A., Design and discovery of small molecules targeting raf-1 kinase. Curr. Pharm. Des., 8, 2269–78 (2002).PubMedCrossRefGoogle Scholar
  38. Lyons, J. F., Wilhelm, S., Hibner, B., and Bollag, G., Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer, 8, 219–225 (2001).PubMedCrossRefGoogle Scholar
  39. Mcdermott, U., Sharma, S. V., Dowell, L., Greninger, P., Montagut, C., Lamb, J., Archibald, H., Raudales, R., Tam, A., Lee, D., Rothenberg, S. M., Supko, J. G., Sordella, R., Ulkus, L. E., Iafrate, A. J., Maheswaran, S., Njauw, C. N., Tsao, H., Drew, L., Hanke, J. H., Ma, X. J., Erlander, M. G., Gray, N. S., Haber, D. A., and Settleman, J., Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc. Natl. Acad. Sci. U. S. A., 104, 19936–19941 (2007).PubMedCrossRefGoogle Scholar
  40. Montagut, C. and Settleman, J., Targeting the RAF-MEKERK pathway in cancer therapy. Cancer Lett., 283, 125–134 (2009).PubMedCrossRefGoogle Scholar
  41. Montagut, C., Sharma, S. V., Shioda, T., Mcdermott, U., Ulman, M., Ulkus, L. E., Dias-Santagata, D., Stubbs, H., Lee, D. Y., Singh, A., Drew, L., Haber, D. A., and Settleman, J., Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res., 68, 4853–4861 (2008).PubMedCrossRefGoogle Scholar
  42. Mordant, P., Loriot, Y., Leteur, C., Calderaro, J., Bourhis, J., Wislez, M., Soria, J. C., and Deutsch, E., Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination. Mol. Cancer Ther., 9, 358–368 (2010).PubMedCrossRefGoogle Scholar
  43. Moreno-Aspitia, A., Clinical overview of sorafenib in breast cancer. Future Oncol., 6, 655–663 (2010).PubMedCrossRefGoogle Scholar
  44. Murphy, D. A., Makonnen, S., Lassoued, W., Feldman, M. D., Carter, C., and Lee, W. M., Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am. J. Pathol., 169, 1875–1885 (2006).PubMedCrossRefGoogle Scholar
  45. Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M. K., Attar, N., Sazegar, H., Chodon, T., Nelson, S. F., Mcarthur, G., Sosman, J. A., Ribas, A., and Lo, R. S., Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, 468, 973–977 (2010).PubMedCrossRefGoogle Scholar
  46. Ott, P. A., Hamilton, A., Min, C., Safarzadeh-Amiri, S., Goldberg, L., Yoon, J., Yee, H., Buckley, M., Christos, P. J., Wright, J. J., Polsky, D., Osman, I., Liebes, L., and Pavlick, A. C., A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One, 5, e15588 (2010).PubMedCrossRefGoogle Scholar
  47. Panka, D. J., Wang, W., Atkins, M. B., and Mier, J. W., The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspaseindependent apoptosis in melanoma cells. Cancer Res., 66, 1611–1619 (2006).PubMedCrossRefGoogle Scholar
  48. Plaza-Menacho, I., Mologni, L., Sala, E., Gambacorti-Passerini, C., Magee, A. I., Links, T. P., Hofstra, R. M., Barford, D., and Isacke, C. M., Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting. J. Biol. Chem., 282, 29230–29240 (2007).PubMedCrossRefGoogle Scholar
  49. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., and Rosen, N., RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 464, 427–430 (2010).PubMedCrossRefGoogle Scholar
  50. Robinson, M. J., and Cobb, M. H. Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol., 9, 180–186 (1997).PubMedCrossRefGoogle Scholar
  51. Sala, E., Mologni, L., Truffa, S., Gaetano, C., Bollag, G. E., and Gambacorti-Passerini, C., BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol. Cancer Res., 6, 751–759 (2008).PubMedCrossRefGoogle Scholar
  52. Salvatore, G., De Falco, V., Salerno, P., Nappi, T. C., Pepe, S., Troncone, G., Carlomagno, F., Melillo, R. M., Wilhelm, S. M., and Santoro, M., BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin. Cancer Res., 12, 1623–1629 (2006).PubMedCrossRefGoogle Scholar
  53. Salvatore, G., Giannini, R., Faviana, P., Caleo, A., Migliaccio, I., Fagin, J. A., Nikiforov, Y. E., Troncone, G., Palombini, L., Basolo, F., and Santoro, M., Analysis of BRAF point mutation and RET/PTC rearrangement refines the fineneedle aspiration diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab., 89, 5175–5180 (2004).PubMedCrossRefGoogle Scholar
  54. Sharma, A., Tran, M. A., Liang, S., Sharma, A. K., Amin, S., Smith, C. D., Dong, C., and Robertson, G. P., Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. Cancer Res., 66, 8200–8209 (2006).PubMedCrossRefGoogle Scholar
  55. Shen, M., Lyne, P., Aquila, B., and Drew, L., Linking molecular characteristics to the pharmacological response of a panel of cancer cell lines to the BRAF inhibitor, AZ628. AACR Meeting Abstracts, 2007, 5249 (2007).Google Scholar
  56. Shields, J. M., Pruitt, K., Mcfall, A., Shaub, A., and Der, C. J., Understanding Ras:’ it ain’t over ‘til it’s over’. Trends Cell. Biol., 10, 147–154 (2000).PubMedCrossRefGoogle Scholar
  57. Socinski, M. A., Multitargeted receptor tyrosine kinase inhibition: An antiangiogenic strategy in non-small cell lung cancer. Cancer Treat. Rev., 37, 611–617 (2011).PubMedCrossRefGoogle Scholar
  58. Stuart, D., Aardalen, K., Venetsanakos, E., Nagel, T., Wallroth, M., Batt, D., Ramurthy, S., Poon, D., Faure, M., Lorenzana, E., Salangsang, F., Dove, J., Garrett, E., Aikawa, M., Kaplan, A., Amiri, P., and Renhowe, P., RAF265 is a potent Raf kinase inhibitor with selective anti-proliferative activity in vitro and in vivo. AACR Meeting Abstracts, 2008, 4876 (2008).Google Scholar
  59. Takezawa, K., Okamoto, I., Yonesaka, K., Hatashita, E., Yamada, Y., Fukuoka, M., and Nakagawa, K., Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res., 69, 6515–6521 (2009).PubMedCrossRefGoogle Scholar
  60. Takle, A. K., Brown, M. J., Davies, S., Dean, D. K., Francis, G., Gaiba, A., Hird, A. W., King, F. D., Lovell, P. J., Naylor, A., Reith, A. D., Steadman, J. G., and Wilson, D. M., The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg. Med. Chem. Lett., 16, 378–381 (2006).PubMedCrossRefGoogle Scholar
  61. Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., Gillette, S., Kong, J., Haass, N. K., Sproesser, K., Li, L., Smalley, K. S., Fong, D., Zhu, Y. L., Marimuthu, A., Nguyen, H., Lam, B., Liu, J., Cheung, I., Rice, J., Suzuki, Y., Luu, C., Settachatgul, C., Shellooe, R., Cantwell, J., Kim, S. H., Schlessinger, J., Zhang, K. Y., West, B. L., Powell, B., Habets, G., Zhang, C., Ibrahim, P. N., Hirth, P., Artis, D. R., Herlyn, M., and Bollag, G., Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. U. S. A., 105, 3041–3046 (2008).PubMedCrossRefGoogle Scholar
  62. Ulivi, P., Arienti, C., Amadori, D., Fabbri, F., Carloni, S., Tesei, A., Vannini, I., Silvestrini, R., and Zoli, W., J. Cell. Physiol., 220, 214–221 (2009).PubMedCrossRefGoogle Scholar
  63. Villanueva, J., Vultur, A., Lee, J. T., Somasundaram, R., Fukunaga-Kalabis, M., Cipolla, A. K., Wubbenhorst, B., Xu, X., Gimotty, P. A., Kee, D., Santiago-Walker, A. E., Letrero, R., D’andrea, K., Pushparajan, A., Hayden, J. E., Brown, K. D., Laquerre, S., Mcarthur, G. A., Sosman, J. A., Nathanson, K. L., and Herlyn, M., Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell, 18, 683–695 (2010).PubMedCrossRefGoogle Scholar
  64. Wan, P. T., Garnett, M. J., Roe, S. M., Lee, S., Niculescu-Duvaz, D., Good, V. M., Jones, C. M., Marshall, C. J., Springer, C. J., Barford, D., and Marais, R., Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 116, 855–867 (2004).PubMedCrossRefGoogle Scholar
  65. Wellbrock, C. and Hurlstone, A., BRAF as therapeutic target in melanoma. Biochem. Pharmacol., 80, 561–567 (2010).PubMedCrossRefGoogle Scholar
  66. 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., and Trail, P. A., 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., 64, 7099–7109 (2004).PubMedCrossRefGoogle Scholar
  67. Xing, J., Liu, R., Xing, M., and Trink, B., The BRAFT1799A mutation confers sensitivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204). Biochem. Biophys. Res. Commun., 404, 958–962 (2011).PubMedCrossRefGoogle Scholar
  68. Yang, F., Van Meter, T. E., Buettner, R., Hedvat, M., Liang, W., Kowolik, C. M., Mepani, N., Mirosevich, J., Nam, S., Chen, M. Y., Tye, G., Kirschbaum, M., and Jove, R., Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. Mol. Cancer Ther., 7, 3519–3526 (2008).PubMedCrossRefGoogle Scholar
  69. Yang, H., Higgins, B., Kolinsky, K., Packman, K., Go, Z., Iyer, R., Kolis, S., Zhao, S., Lee, R., Grippo, J. F., Schostack, K., Simcox, M. E., Heimbrook, D., Bollag, G., and Su, F., RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res., 70, 5518–5527 (2010).PubMedCrossRefGoogle Scholar
  70. Yoon, S. and Seger, R., The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors, 24, 21–44 (2006).PubMedCrossRefGoogle Scholar
  71. Zhang, W., Konopleva, M., Shi, Y.X., McQueen, T., Harris, D., Ling, X., Estrov, Z., Quintas-Cardama, A., Small, D., Cortes. J., Andreeff, M., Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J. Natl. Cancer Inst., 100, 184–198 (2008).PubMedCrossRefGoogle Scholar
  72. Zitzmann, K., De Toni, E., Von Ruden, J., Brand, S., Goke, B., Laubender, R. P., and Auernhammer, C. J., The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr. Relat. Cancer, 18, 277–285 (2011).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2012

Authors and Affiliations

  1. 1.Chemical Kinomics Research CenterKorea Institute of Science and TechnologySeoulKorea
  2. 2.Future Convergence Research DivisionKorea Institute of Science and TechnologySeoulKorea

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