Kinase components of the Ras-MAPK signaling cascade as potential targets for therapeutic intervention

Drugs of the Future

Volumn 28, Issue 12, 2003, Pages 1211-1226

  Berger, Dan M ^a   Mallon, Robert ^a  

^a WYETH RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

10 HYMENIALDISINE; 2 (2 AMINO 3 METHOXYPHENYL)CHROMONE; 2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; ANTISENSE OLIGODEOXYNUCLEOTIDE; ANTISENSE OLIGONUCLEOTIDE; CGP 69846A; EPIGALLOCATECHIN GALLATE; GW 5074; KF 25706; KF 58333; L 779450; L 783277; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; N [5 (3 DIMETHYLAMINOBENZAMIDO) 2 METHYLPHENYL] 4 HYDROXYBENZAMIDE; NOVOBIOCIN; PROTEIN INHIBITOR; RADICICOL; RAF PROTEIN; RAS PROTEIN; RO 09 2210; SORAFENIB; THEAFLAVIN 3,3' DIGALLATE; UNCLASSIFIED DRUG;

ANIMAL CELL; CELL STRAIN COS1; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ANALYSIS;

EID: 0442294081     PISSN: 03778282     EISSN: None     Source Type: Journal    
DOI: 10.1358/dof.2003.028.12.857391     Document Type: Review

References (131)

1. Malumbres, M., Barbacid, M. RAS oncogenes: The first 30 years. Nat Rev Cancer 2003, 3: 459-65.
2. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003, 3: 11-22.
3. Bos, J.L. Ras oncogenes in human cancer: A review. Cancer Res 1989, 49: 4682-9.
4. Shields, J.M., Pruitt, K., McFall, A. et al. Understanding Ras: "It ain't over 'til it's over". Trends Cell Biol 2000, 10: 147-54.
5. Ellis, R.W., Defeo, D., Shih, T.Y. et al. The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature 1981, 292: 506-11.
6. Perucho, M., Goldfarb, M., Shimizu, K., Lama, C., Fogh, J. and Wigler, M. Human-tumor-derived cell lines contain common and different transforming genes. Cell 1981, 27: 467-76.
7. Santos, E., Martin-Zanca, D., Reddy, E.P., Pierotti, M.A., Della Porta, G., Barbacid, M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 1984, 223: 661-4.
8. Krengel, U., Schlichting, L., Scherer, A. et al. Three-dimensional structures of H-ras p21 mutants: Molecular basis for their inability to function as signal switch molecules. Cell 1990, 62: 539-48.
9. Lowy, D.R., Willumsen, B.M. Function and regulation of ras. Annu Rev Biochem 1993, 62: 851-91.
10. Hancock, J.F., Magee, A.I., Childs, J.E. and Marshall, C.J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989, 57: 1167-77.
11. Kolch, W. Meaningful relationships: The regulation of the Ras/Raf/MEK/ ERK pathway by protein interactions. Biochem J 2000, 351 (Pt. 2): 289-305.
12. Kolch, W. Ras/Raf signalling and emerging pharmacotherapeutic targets. Expert Opin Pharmacol 2002, 3: 709-18.
13. Hagemann, C., Rapp, U.R. Isotype-specific functions of raf kinases. Exp Cell Res 1999, 253: 34-46.
14. Chong, H., Vikis, H.G., Guan, K.-L. Mechanisms of regulating the Raf kinase family. Cell Signal 2003, 15: 463-9.
15. Chong, H., Lee, J., Guan, K.L. Positive and negative regulation of raf kinase activity and function by phosphorylation. EMBO J 2001, 20: 3716-27.
16. Fabian, J.R., Daar, I.O., Morrison, D.K. Critical tyrosine residues regulate the enzymatic and biological activity of raf-1 kinase. Mol Cell Biol 1993, 13: 7170-9.
17. Marais, R., Wynne, J., Treisman, R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 1993, 73: 381-93.
18. Morrison, D.K., Heidecker, G., Rapp, U.R., Copeland, T.D. Identification of the major phosphorylation sites of the Raf-1 kinase. J Biol Chem 1993, 268: 17309-16.
19. Mason, C.S., Springer, C.J., Cooper, R.G., Superti-Furga, G., Marshall, C.J., Marais, R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 1999, 18: 2137-48.
20. Dhillon, A.S., Meikle, S., Yazici, Z., Eulitz, M., Kolch, W. Regulation of Raf-1 activation and signalling by dephosphorylation. EMBO J 2002, 21: 64-71.
21. Kolch, W. To be or not to be: A question of B-Raf? Trends Neurosci 2001, 24: 498-500.
22. Abraham, D., Podar, K., Pacher, M. et al. Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation. J Biol Chem 2000, 275: 22300-4.
23. Yeung, K., Seitz, T., Li, S. et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 1999, 401: 173-7.
24. Chang, F., Steelman, L.S., Lee, J.T. et al. Signal transduction mediated by the RasRafMEKERK pathway from cytokine receptors to transcription factors: Potential targeting for therapeutic intervention. Leukemia 2003 17: 1263-93.
25. Dhillon, A.S., Kolch, W. Untying the regulation of the Raf-1 kinase. Arch Biochem Biophys 2002, 404: 3-9.
26. Morrison, D.K. KSR: A MAPK scaffold of the Ras pathway? J Cell Sci 2001, 114: 1609-12.
27. Baccarini, M. An old kinase on a new path: Raf and apoptosis. Cell Death Differ 2002, 9: 783-5.
28. Pritchard, C.A., Bolin, L., Slattery, R., Murray, R., McMahon, M. Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Curr Biol 1996, 6: 614-7.
29. Wojnowski, L., Zimmer, A.M., Beck, T.W. et al. Endothelial apoptosis in Braf-deficient mice. Nat Genet 1997, 16: 293-7.
30. Huser, M., Luckett, J., Chiloeches, A. et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J 2001, 20: 1940-51.
31. Murakami, M.S., Morrison, D.K. Raf-1 without MEK? Science's STKE 2001, PE30.
32. Chen, J., Fujii, K., Zhang, L., Roberts, T., Fu, H. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci USA 2001, 98: 7783-8.
33. Shimamura, A., Ballif, B.A., Richards, S.A., Blenis, J. Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr Biol 2000, 10: 127-35.
34. Wang, H.G., Miyashita, T., Takayama, S. et al. Apoptosis regulation by interaction of Bcl-2 protein and Raf-1 kinase. Oncogene 1994, 9: 2751-6.
35. Herrera, R., Sebolt-Leopold, J.S. Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends Mol Med 2002, 8: S27-31.
36. Mark, G.E., Rapp, U.R. Primary structure of v-raf: Relatedness to the src family of oncogenes. Science 1984, 224: 285-9.
37. Davies, H., Bignell, G.R., Cox, C. et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417: 949-54.
38. Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K.W., Vogelstein, B., Velculescu, V.E. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002, 418: 934.
39. Smalley, K.S. A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 2003, 104: 527-32.
40. Dhanasekaran, N., Premkumar Reddy, E. Signaling by dual specificity kinases. Oncogene 1998, 17: 1447-55.
41. English, J., Pearson, G., Wilsbacher, J. et al. New insights into the control of MAP kinase pathways. Exp Cell Res 1999, 253: 255-70.
42. Giroux, S., Tremblay, M., Bernard, D. et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol 1999, 9: 369-72.
43. Bélanger, L.F., Roy, S., Tremblay, M. et al. Mek2 is dispensable for mouse growth and development. Mol Cell Biol 2003, 23: 4778-87.
44. Mansour, S.J., Matten, W.T., Hermann, A.S. et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 1994, 265: 966-70.
45. English, J.M., Cobb, M.H. Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 2002, 23: 40-5.
46. Zhang, F., Strand, A., Robbins, D., Cobb, M.H., Goldsmith, E.J. Atomic structure of the MAP kinase ERK2 at 2.3 Angstrom resolution. Nature 1994, 367: 704-11.
47. Ferrell, J.E., Jr. Tripping the switch fantastic: How a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem Sci 1996, 21: 460-6.
48. Huang, C.Y., Ferrell, J.E., Jr. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 1996, 93: 10078-83.
49. Blume-Jensen, P., Hunter, T. Oncogenic kinase signalling. Nature 2001, 411: 355-65.
50. Deng, C., Lu, Q., Zhang, Z. et al. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum 2003, 48: 746-56.
51. Giardiello, F.M. Sulindac and polyp regression. Cancer Metast Rev 1994, 13: 279-83.
52. Luk, G.D. Prevention of gastrointestinal cancer - The potential role of NSAIDs in colorectal cancer. Schweiz Med Wschr 1996, 126: 801-12.
53. Piazza, G.A., Rahm, A.K., Finn, T.S. et al. Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 1997, 57: 2452-9.
54. Herrmann, C., Block, C., Geisen, C. et al. Sulindac sulfide inhibits Ras signaling. Oncogene 1998, 17: 1769-76.
55. Gao, H., Huang, K.C., Yamasaki, E.F., Chan, K.K., Chohan, L., Snapka, R.M. XK469, a selective topoisomerase IIbeta poison. Proc Natl Acad Sci USA 1999, 96: 12168-73.
56. Kessel, D., Horwitz, J.P. Pro-apoptotic interactions between XK469 and the peripheral benzodiazepine receptor. Cancer Lett 2001, 168: 141-4.
57. Ding, Z., Parchment, R.E., LoRusso, P.M. et al. The investigational new drug XK469 induces G2-M cell cycle arrest by p53-dependent and -independent pathways. Clin Cancer Res 2001, 7: 3336-42.
58. Lin, H., Subramanian, B., Nakeff, A., Chen, B.D. XK469, a novel antitumor agent, inhibits signaling by the MEK/MAPK signaling pathway. Cancer Chemother Pharmacol 2002, 49: 281-6.
59. Pintus, G., Tadolini, B., Posadino, A.M. et al. Inhibition of the MEK/ ERK signaling pathway by the novel antimetastatic agent NAMI-A down regulates c-myc gene expression and endothelial cell proliferation. Eur J Biochem 2002, 269: 5861-70.
60. Sanna, B., Debidda, M., Pintus, G. et al. The anti-metastatic agent imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate induces endothelial cell apoptosis by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway. Arch Biochem Biophys 2002, 403: 209-18.
61. Schulte, T.W., Blagosklonny, M.V., Romanova, L. et al. Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signaling pathway. Mol Cell Biol 1996, 16: 5839-45.
62. Blagosklonny, M.V. Hsp-90-associated oncoproteins: Multiple targets of geldanamycin and its analogs. Leukemia 2002, 16: 455-62.
63. Lee, J.T. Jr., McCubrey, J.A. The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia 2002, 16: 486-507.
64. Marcu, M.G., Chadli, A., Bouhouche, I., Catelli, M., Neckers, L.M. The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J Biol Chem 2000, 275: 37181-6.
65. Soga, S., Neckers, L.M., Schulte, T.W. et al. KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res 1999, 59: 2931-8.
66. Chung, J.Y., Park, J.O., Phyu, H., Dong, Z., Yang, C.S. Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3′-digallate. FASEB J 2001, 15: 2022-4.
67. Hall-Jackson, C.A., Eyers, P.A., Cohen, P. et al. Paradoxical activation of Raf by a novel Raf inhibitor. Chem Biol 1999, 6: 559-68.
68. Heimbrook, D.C., Huber, H.E., Stirdivant, S.M. et al. Identification of potent, selective inhibitors of Raf protein kinase. 89th Annu Meet Am Assoc Cancer Res (March 28-April 1, New Orleans) 1998, Abst 3793.
69. Cuenda, A., Rouse, J., Doza, Y.N. et al. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett 1995, 364: 229-33.
70. Lackey, K., Cory, M., Crosby, R.M. et al. The identification of cRaf1 kinase inhibitors as anti-cancer agents. 90th Annu Meet Am Assoc Cancer Res (April 10-14, Philadelphia) 1999, Abst 828.
71. Lackey, K., Cory, M., Davis, R. et al. The discovery of potent cRaf1 kinase inhibitors. Bioorg Med Chem Lett 2000, 10: 223-6.
72. Smith, R.A., Barbosa, J., Blum, C.L. 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 2001, 11: 2775-8.
73. Lowinger, T.B., Riedl, B., Dumas, J., Smith, R.A. Design and discovery of small molecules targeting raf-1 kinase. Curr Pharm Design 2002, 8: 2269-78.
74. Lowinger, T.B., Riedl, B., Wood, J. et al. Discovery of a novel class of potent Raf kinase inhibitors: Structure activity relationships. NCI-EORTC-AACR Symp (Nov 7-10, Amsterdam) 2000, Abst 335.
75. Riedl, B., Lowinger, T.B., Bankston, D. et al. Potent Raf kinase inhibitors from the diphenylurea class: Structure activity relationships. 91st Annu Meet Am Assoc Cancer Res (April 1-5, San Francisco) 2000, Abst 4956.
76. Wilhelm S.M., Housley T., Kennure, N. et al. BAY 43-9006: A novel Raf-1 kinase inhibitor (RKI), blocks the Raf/MEK/ERK pathway in tumor cells. 91st Annu Meet Am Assoc Cancer Res (April 1-5, San Francisco) 2000, Abst 4957.
77. Carter, C.A., Gianpaolo-Ostravage C., Hibner, B. et al. Antitumor efficacy of the orally active Raf kinase inhibitor BAY-43-9006 in human tumor xenograft models. 91st Annu Meet Am Assoc Cancer Res (April 1-5, San Francisco) 2000, Abst 4954.
78. Sorbera, L.A., Castaner, J. Bozzo, J., Leeson, P.A. Bay-43-9006. Drugs Fut 2002, 27: 1141-7.
79. Wilhelm, S., Chien, D.-S. BAY43-9006: Preclinical data. Curr Pharm Design 2002, 8: 2255-7.
80. Hotte, S.J., Hirte, H.W. Bay 43-9006: Early clinical data in patients with advanced solid malignancies. Curr Pharm Design 2002, 8: 2249-53.
81. Strumberg, D., Awada, A., Piccart, M. et al. Final report of the phase 1 clinical program of the novel raf kinase inhibitor BAY 43-9006 in patients with refractory solid tumors. Proc Am Soc Clin Oncol 2003, 22: Abst 813.
82. Hilger, R.A., Kredtke, S., Hedley, D. et al. Inhibition of ERK phosphorylation and clinical outcome in patients treated with the Raf kinase inhibitor BAY 43-9006. Proc Am Soc Clin Oncol 2002, 21: Abst 1916.
83. Flaherty, K. T., Lee, R.J., Humphries, R., O'Dwyer, P.J., Schiller, J. Phase I trial of BAY 43-9006 in combination with carboplatin (C) and paclitaxel (P). Proc Am Soc Clin Oncol 2003, 22: Abst 2854.
84. Siu, L., Awada, A., Takimoto, C.H. et al. Phase I study of oral raf-1 kinase inhibitor BAY 43-9006 with gemcitabine in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2003, 22: Abst 828.
85. Monia, B.P., Johnston, J.F., Geiger, T., Muller, M., Fabbro, D. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nat Med 1996, 2: 668-75.
86. McPhillips, F., Mullen, P., Monia, B.P. et al. Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. Brit J Cancer 2001, 85: 1753-8.
87. Stevenson, J.P., Yao, K.S., Gallagher, M. et al. Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A). J Clin Oncol 1999, 17: 2227-36.
88. O'Dwyer, P.J., Stevenson, J.P., Gallagher, M. et al. C-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A). Clin Cancer Res 1999, 5: 3977-82.
89. Cunningham, C.C., Holmlund, J.T., Schiller, J.H. et al. A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 2000, 6: 1626-31.
90. Rudin, C.M., Holmlund, J., Fleming, G.F. et al. Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. Clin Cancer Res 2001, 7: 1214-20.
91. Cripps, M.C., Figueredo, A.T., Oza, A.M. et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer. A National Cancer Institute of Canada Clinical Trials Group study. Clin Cancer Res 2002, 8: 2188-92.
92. Tolcher, A.W., Reyno, L., Venner, P.M. et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res 2002, 8: 2530-5.
93. Coudert, B., Anthoney, A., Fiedler, W. et al. Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report. Eur J Cancer 2001, 37: 2194-8.
94. Stevenson, J.P., Gallagher, M., Ryan, W. et al. Phase I trial of the c-raf-1 antisense oligonucleotide (ODN) ISIS 5132 administered as a 21-day continuous infusion in combination with 5-fluorouracil (5-FU) and leucovorin (LV) as a daily x 5 IV bolus. AACR-NCI-EORTC Symp (Nov 16-19, Washington, DC) 1999, Abst 579.
95. Gokhale, P.C., Zhang, C., Newsome, J.T. et al. Pharmacokinetics, toxicity, and efficacy of ends-modified raf antisense oligodeoxyribonucleotide encapsulated in a novel cationic liposome. Clin Cancer Res 2002, 8: 3611-21.
96. Mewani, R., Tang, W., Rahman, A., Dritschilo, A., Ahmad, I., Kasid, U., Gokhale, P.C. Enhanced antitumor activity of liposome-entrapped antisense raf oligonucleotide (LErafAON) in combination with chemotherapeutic agents. 93rd Annu Meet Am Assoc Cancer Res (April 6-10, San Francisco) 2002, Abst 2863.
97. Pei, J., Zhang, C., Gokhale, P.C., Rahman, A., Dritschilo, A., Ahmad, I., Kasid, U. Antitumor activity of a combination of liposomal antisense Raf oligodeoxyribonucleotide (LErafAON) and chemotherapeutic drug cisplatin, mitoxantrone or epirubicin. 93rd Annu Meet Am Assoc Cancer Res (April 6-10, San Francisco) 2002, Abst 2055.
98. Pei, J., Zhang, C., Gokhale, P., Rahman, A., Dritschilo, A., Ahmad, I., Kasid, U. Enhanced effects of a novel liposome-based antisense raf oligodeoxyribonucleotide (LErafAON) in combination with taxotere or gemcitabine. 1st Int Congr Targeted Ther (Washington, DC) 2002, Abst 10.
99. Rudin, C., Bertucci, D., Strauss, L. et al. Liposome-encapsulated C-Raf antisense oligonucleotide (LErafAON) in patients with advanced solid tumors: Phase I study of weekly infusion. Proc Am Soc Clin Oncol 2002, 21: Abst 1845.
100. Rudin, C.M., Marshall, J., Huang, C.H. et al. Delivery of a C-Raf antisense oligodeoxynucleotide (LErafAON) by intermittent bolus dosing (weekly infusions) in patients with advanced solid tumors: A phase I study. EORTC-NCI-AACR Symp Mol Targets Cancer Ther (Nov 19-22, Frankfurt) 2002, Abst 473.
101. Dritschilo, A., Huang, C., Strauss, L. et al. Liposome-encapsulated c-raf antisense oligodeoxynucleotide (LErafAON) in patients with advanced solid tumors: Phase I study of daily infusion during radiation therapy. Proc Am Soc Clin Oncol 2002, 21: Abst 107.
102. Williams, D.H., Wilkinson, S.E., Purton, T., Lamont, A., Flotow, H., Murray, E.J. Ro 09-2210 exhibits potent anti-proliferative effects on activated T cells by selectively blocking MKK activity. Biochemistry 1998, 37: 9579-85.
103. Zhao, A., Lee, S.H., Mojena, M. et al. Resorcylic acid lactones: Naturally occurring potent and selective inhibitors of MEK. J Antibiot 1999, 52: 1086-94.
104. Tasdemir, D., Mallon, R., Greenstein, M. et al. Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). J Med Chem 2002, 45: 529-32.
105. Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J., Saltiel, A.R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 1995, 92: 7686-9.
106. Alessi, D.R., Cuenda, A., Cohen, P., Dudley, D.T., Saltiel, A.R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 1995, 270: 27489-94.
107. Kamakura, S., Moriguchi, T., Nishida, E. Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem 1999, 274: 26563-71.
108. Wang, X., Studzinski, G.P. Phosphorylation of raf-1 by kinase suppressor of ras is inhibited by "MEK-specific" inhibitors PD 098059 and U0126 in differentiating HL60 cells. Exp Cell Res 2001, 268: 294-300.
109. Borsch-Haubold, A.G., Pasquet, S., Watson, S.P. Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem 1998, 273: 28766-72.
110. Favata, M.F., Horiuchi, K.Y., Manos, E.J. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998, 273: 18623-32.
111. Davies, S.P., Reddy, H., Caivano, M., Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000, 351: 95-105.
112. Ahn, N.G., Nahreini, T.S., Tolwinski, N.S., Resing, K.A. Pharmacologic inhibitors of MKK1 and MKK2. Method Enzymol 2001, 332: 417-31.
113. Mody, N., Leitch, J., Armstrong, C., Dixon, J., Cohen, P. Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett 2001, 502: 21-4.
114. Duncia, J.V., Santella, J.B., 3rd, Higley, C.A. et al. MEK inhibitors: The chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 1998, 8: 2839-44.
115. Zhang, N., Wu, B., Powell, D. et al. Synthesis and structure-activity relationships of 3-cyano-4-(phenoxyanilino)quinolines as MEK (MAPKK) inhibitors. Bioorg Med Chem Lett 2000, 10: 2825-8.
116. Zhang, N., Wu, B., Eudy, N. et al. MEK (MAPKK) inhibitors. Part 2: Structure-activity relationships of 4-anilino-3-cyano-6,7-dialkoxyquinolines. Bioorg Med Chem Lett 2001, 11: 1407-10.
117. Berger, D.M., Dutia, M., Powell, D.W. et al. Synthesis and evaluation of 4-anilino substituted 3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. 224th ACS Natl Meet (Aug 18-22, Boston) 2002, MEDI-105.
118. Dutia, M., Berger, D.M., Powell, D.W. et al. Design and synthesis of 6,7-substituted 4-anilino-3-quinolinecarbonitriles as potent inhibitors of kinases of the Ras-MAPK signaling cascade. 224th ACS Natl Meet (Aug 18-22, Boston) 2002, MEDI-104.
119. Berger, D., Dutia, M., Powell, D. et al. Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. Bioorg Med Chem Lett 2003, 13: 3031-4.
120. Sebolt-Leopold, J.S., Dudley, D.T., Herrera, R. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 1999, 5: 810-6.
121. Trachet, E., Przybranowski, S., Howard, C. et al. In vivo evaluation of MEK inhibitor, CI-1040 (PD 0184352), against a panel of human pancreatic tumor xenografts. 93rd Annu Meet Am Assoc Cancer Res (April 6-10, San Francisco) 2002, Abst 5426.
122. Mitchell, D.Y., Reid, J.M., Parchment, R.E. et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of the oral MEK inhibitor, CI-1040, following multiple dose administration to patients with advanced cancer. Proc Am Soc Clin Oncol 2002, 21: Abst 320.
123. LoRusso, P.M., Adjei, A.A., Meyer, M.B. et al. A phase I clinical and pharmacokinetic evaluation of the oral MEK inhibitor, CI-1040, administered for 21 consecutive days, repeated every 4 weeks in patients with advanced cancer. Proc Am Soc Clin Oncol 2002, 21: Abst 321.
124. Waterhouse, D.M., Rinehart, J. Adjei, A.A. et al. A phase 2 study of an oral MEK inhibitor, CI-1040, in patients with advanced nonsmall-cell lung, breast, colon or pancreatic cancer. Proc Am Soc Clin Oncol 2003, 22: Abst 816.
125. IMS R&D Focus Database, Accession Number 2014057, Agouron USA, IMS World Publications, Plymouth Meeting, PA, 2003.
126. O'Dwyer, M.E., Mauro, M.J., Druker, B.J. STI571 as a targeted therapy for CML. Cancer Invest 2003, 21: 429-38.
127. Dancey, J., Sausville, E.A. Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2003, 2: 296-313.
128. Muhsin, M., Graham, J., Kirkpatrick, P. Fresh from the pipeline: Gefitinib. Nat Rev Cancer 2003, 3: 556-7.
129. Weinstein-Oppenheimer, C.R., Blalock, W.L., Steelman, L.S., Chang, F., McCubrey, J.A. The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacol Ther 2000, 88: 229-79.
130. Dancey, J.E. Agents targeting ras signaling pathway. Curr Pharm Design 2002, 8: 2259-67.
131. Lee, J.T. Jr, McCubrey, J.A. Targeting the Raf kinase cascade in cancer therapy - Novel molecular targets and therapeutic strategies. Expert Opin Ther Targets 2002, 6: 659-78.