Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1, 1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E

Journal of Medicinal Chemistry

Volumn 55, Issue 3, 2012, Pages 1082-1105

  Rowbottom, Martin W ^a   Faraoni, Raffaella ^a   Chao, Qi ^a   Campbell, Brian T ^a   Lai, Andiliy G ^a   Setti, Eduardo ^a   Ezawa, Maiko ^a   Sprankle, Kelly G ^a   Abraham, Sunny ^a   Tran, Lan ^a   Struss, Brian ^a   Gibney, Michael ^a   Armstrong, Robert C ^a   Gunawardane, Ruwanthi N ^a   Nepomuceno, Ronald R ^a   Valenta, Ianina ^a   Hua, Helen ^a   Gardner, Michael F ^a   Cramer, Merryl D ^a   Gitnick, Dana ^a   Insko, Darren E ^a   Apuy, Julius L ^a   Jones Bolin, Susan ^b   Ghose, Arup K ^b   Herbertz, Torsten ^b   Ator, Mark A ^b   Dorsey, Bruce D ^b   Ruggeri, Bruce ^b   Williams, Michael ^b   Bhagwat, Shripad ^a   James, Joyce ^a   Holladay, Mark W ^a   more..

^a Ambit Biosciences   (United States)

^b CEPHALON INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (3 CYCLOPENTYLISOXAZOL 5 YL) 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 (3 TERT BUTYLPHENYL) 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY]PHENYL)UREA; 1 (4 TERT BUTYLPHENYL) 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 (5 CYCLOPENTYLISOXAZOL 3 YL) 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 (5 TERT BUTYLISOXAZOL 3 YL) 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 [3 (1,1 DIFLUOROETHYL)ISOXAZOL 5 YL] 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 [3 (1,3 DIFLUORO 2 METHYLPROPAN YLISOXAZOL 5 YL] 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 [3 (2 CYANOPROPAN 2 YL)ISOXAZOL 5 YL] 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 (3 ISOPROPYL ISOXAZOL 5 YL)UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 (3 PHENYLISOX AZOL 5 YL)UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 (3 PHENYLISOXAZOL 5 YL)UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 (5 ISOPROPYL ISOXAZOL 3 YL)UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 (5 METHYLISOXAZOL 3 YL)UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 (5 PHENYL ISOXAZOL 3 YL)UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [3 (1,1,1 TRIFLUORO 2 METHYLPROPAN 2 YL)ISOXAZOL 5 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [3 (2 FLUOROPROPAN 2 YL)ISOXAZOL 5 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [3 (TRIFLUOROMETHYL)ISOXAZOL 5 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [3 [1 (TRIFLUOROMETHYL)CYCLOBUTYL]ISOXAZOL 5 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [5 (1 HYDROXY 2 METHYLPROPAN 2 YL)ISOXAZOL 3 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [5 (1 METHOXY 2 METHYLPROPAN 2 YL)ISOXAZOL 3 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL] 3 [5 (2 FLUORO PROPAN 2 YL)ISOXAZOL 3 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLTHIO)PHENYL] 3 [3 (2 FLUORO PROPAN 2 YL)ISOXAZOL 5 YL]UREA; 1 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLTHIO)PHENYL] 3 [5 [1 (TRIFLUOROMETHYL)CYCLOPROPYL]ISOXAZOL 3 YL]UREA; 1 [5 (1,3 DIFLUORO 2 METHYLPROPAN 2 YL)ISOXAZOL 3 YL] 3 [3 (6,7 DIMETHOXYQUINAZOLIN 4 YLOXY)PHENYL]UREA; B RAF KINASE; CEP 32496; CHIR 265; TERT BUTYL ALCOHOL; UNCLASSIFIED DRUG; UNINDEXED DRUG; UREA DERIVATIVE; VEMURAFENIB;

ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CONTROLLED STUDY; CYTOTOXICITY; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SENSITIVITY; DRUG STRUCTURE; FLUORINATION; HUMAN; HUMAN CELL; IN VIVO STUDY; NONHUMAN; PHARMACODYNAMICS; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BINDING, COMPETITIVE; CELL LINE, TUMOR; CELL PROLIFERATION; DOGS; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HUMANS; ISOXAZOLES; MACACA FASCICULARIS; MALE; MICE; MICE, NUDE; MICROSOMES, LIVER; MODELS, MOLECULAR; MUTATION; NEOPLASM TRANSPLANTATION; PROTO-ONCOGENE PROTEINS B-RAF; QUINAZOLINES; RATS; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS;

EID: 84863393355     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2009925     Document Type: Article

References (42)

1. Peyssonnaux, C.; Eychéne, A. The Raf/MEK/ERK pathway: New concepts of activation Biol. Cell. 2001, 93, 53-62 (Pubitemid 33040860)
2. Davies, H.; Bignell, G. R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M. J.; Bottomley, W.; Davis, N.; Dicks, E.; Ewing, R.; Floyd, Y.; Gray, K.; Hall, S.; Hawes, R.; Hughes, J.; Kosmidou, V.; Menzies, A.; Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.; Gusterson, B. A.; Cooper, C.; Shipley, J.; Hargrave, D.; Pritchard-Jones, K.; Maitland, N.; Chenevix-Trench, G.; Riggins, G. J.; Bigner, D. D.; Palmieri, G.; Cossu, A.; Flanagan, A.; Nicholson, A.; Ho, J. W. C.; Leung, S. Y.; Yuen, S. T.; Weber, B. L.; Seigler, H. F.; Darrow, T. L.; Paterson, H.; Marais, R.; Marshall, C. J.; Wooster, R.; Stratton, M. R.; Futreal, P. A. Mutations of the BRAF gene in human cancer Nature 2002, 417, 949-954 (Pubitemid 34716871)
3. Lee, J. H.; Lee, E.-S.; Kim, Y.-S. Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: A meta-analysis Cancer 2007, 110, 38-46 (Pubitemid 46986416)
4. Samowitz, W. S.; Sweeney, C.; Herrick, J.; Albertsen, H.; Levin, T. R.; Murtaugh, M. A.; Wolff, R. K.; Slattery, M. L. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers Cancer Res. 2005, 65, 6063-6069
5. Houben, R.; Becker, J. C.; Kappel, A.; Terheyden, P.; Bröcker, E.-B.; Goetz, R.; Rapp, U. R. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis J. Carcinog. 2004, 3, 6-18
6. V600E: Implications for carcinogenesis and molecular therapy Mol. Cancer Ther. 2011, 10, 385-394
7. Ramurthy, S.; Aikawa, M.; Amiri, P.; Costales, A.; Hashash, A.; Jansen, J. M.; Lin, S.; Ma, S.; Renhowe, P. A.; Shafer, C. M.; Subramanian, S.; Sung, L.; Verhagen, J. Design and synthesis of 5,6-fused heterocyclic amides as Raf kinase inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 3286-3289
8. V600E. Part 1: The development of selective, orally available, and efficacious inhibitors ACS Med. Chem. Lett. 2011, 2, 342-347
9. V600E kinase Bioorg. Med. Chem. Lett. 2011, 21, 1243-1247
10. Gould, A. E.; Adams, R.; Adhikari, S.; Aertgeerts, K.; Afroze, R.; Blackburn, C.; Calderwood, E. F.; Chau, R.; Chouitar, J.; Duffey, M. O.; England, D. B.; Farrer, C.; Forsyth, N.; Garcia, K.; Gaulin, J.; Greenspan, P. D.; Guo, R.; Harrison, S. J.; Huang, S.-C.; Iartchouk, N.; Janowick, D.; Kim, M.-S.; Kulkarni, B.; Langston, S. P.; Liu, J. X.; Ma, L.-T.; Menon, S.; Mizutani, H.; Paske, E.; Renou, C. C.; Rezaei, M.; Rowland, R. S.; Sintchak, M. D.; Smith, M. D.; Stroud, S. G.; Tregay, M.; Tian, Y.; Veiby, O. P.; Vos, T. J.; Vyskocil, S.; Williams, J.; Xu, T.; Yang, J. J.; Yano, J.; Zeng, H.; Zhang, D. M.; Zhang, Q.; Galvin, K. M. Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors J. Med. Chem. 2011, 54, 1836-1846
11. V600EBRAF Cancer Res. 2010, 70, 8036-8044
12. Zambon, A.; Ménard, D.; Suijkerbuijk, B. M. J. M.; Niculescu-Duvaz, I.; Whittaker, S.; Niculescu-Duvaz, D.; Nourry, A.; Davies, L.; Manne, H. A.; Lopes, F.; Preece, N.; Hedley, D.; Ogilvie, L. M.; Kirk, R.; Marais, R.; Springer, C. J. Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors. J. Med. Chem. 2010, 53, 5639-5655 (and references contained therein).
13. Wang, X.; Berger, D. M.; Salaski, E. J.; Torres, N.; Dutia, M.; Hanna, C.; Hu, Y.; Levin, J. L.; Powell, D.; Wojciechowicz, D.; Collins, K.; Frommer, E.; Lucas, J. Indazolylpyrazolopyrimidines as highly potent B-Raf inhibitors with in vivo activity J. Med. Chem. 2010, 53, 7874-7878
14. V600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression Cancer Res. 2009, 69, 3042-3051
15. Smith, A. L.; DeMorin, F. F.; Paras, N. A.; Huang, Q.; Petkus, J. K.; Doherty, E. M.; Nixey, T.; Kim, J. L.; Whittington, D. A.; Epstein, L. F.; Lee, M. R.; Rose, M. J.; Babij, C.; Fernando, M.; Hess, K.; Le, Q.; Beltran, P.; Carnahan, J. Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline J. Med. Chem. 2009, 52, 6189-6192
16. Ramurthy, S.; Subramanian, S.; Aikawa, M.; Amiri, P.; Costales, A.; Dove, J.; Fong, S.; Jansen, J. M.; Levine, B.; Ma, S.; McBride, C. M.; Michaelian, J.; Pick, T.; Poon, D. J.; Girish, S.; Shafer, C. M.; Stuart, D.; Sung, L.; Renhowe, P. A. Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors J. Med. Chem. 2008, 51, 7049-7052
17. See the Novartis website (http://www.novartisoncology.com/research- innovation/pipeline/raf265) (accessed April 10, 2011) and the ClinicalTrials.gov website (http://www.clinicaltrials.gov) (NCT00304525, accessed on April 10, 2011). Also see: Stuart, D.; Aardalen, K.; Venetsanakos, E.; Lorenzana, E.; Salangsang, F.; Nagel, T.; Wallroth, M.; Batt, D.; Ramurthy, S.; Poon, D.; Faure, M.; Aikawa, M.; Dove, J.; Garrett, L.; Kaplan, A.; Amiri, P.; Pryer, N.; Renhowe, P. RAF265 is a potent Raf inhibitor with selective anti-proliferative activity in vitro and in vivo. AACR Annu. Meet. 2008, Abstract 4876.
18. See the Exelixis website (http://www.exelixis.com/pipeline) (accessed April 10, 2011) and the ClinicalTrials.gov website (http://www.clinicaltrials. gov) (NCT01086267, accessed on April 10, 2011). See also: Schwartz, G. L.; Robertson, S.; Shen, A.; Wang, E.; Pace, L.; Dials, H.; Mendelson, D.; Shannon, P.; Gordon, M. A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors. J. Clin. Oncol. 2009, 27, 15sAbstr. 3513.
19. See the GlaxoSmithKline website (http://www.gsk.com/investors/pp- pipeline-standard) (accessed April 10, 2011) and the ClinicalTrials.gov website (http://www.clinicaltrials.gov) (NCT01227889, accessed on April 10, 2011). See also: Kefford, R.; Arkenau, H.; Brown, M. P.; Millward, M.; Infante, J. R.; Long, G. V.; Ouellet, D.; Curtis, M.; Lebowitz, P. F.; 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. 2010, 28, 15sAbstr. 8503.
20. Chapman, P. B.; Hauschild, A.; Robert, C.; Haanen, J. B.; Ascierto, P.; Larkin, J.; Dummer, R.; Garbe, C.; Testori, A.; Maio, M.; Hogg, D.; Lorigan, P.; Lebbe, C.; Jouary, T.; Schadendorf, D.; Ribas, A.; O'Day, S. J.; Sosman, J. A.; Kirkwood, J. M.; Eggermont, A. M. M.; Dreno, B.; Nolop, K.; Li, J.; Nelson, B.; Hou, J.; Lee, R. J.; Flaherty, K. T.; McArthur, G. A. Improved survival with vemurafenib in melanoma with BRAF V600E mutation N. Engl. J. Med. 2011, 364, 2507-2516
21. Vultur, A.; Villanueva, J.; Herlyn, M. Targeting BRAF in advanced melanoma: A first step toward manageable disease Clin. Cancer Res. 2011, 17, 1658-1663
22. 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.; Chapman, P. B. Inhibition of mutated, activated BRAF in metastatic melanoma N. Engl. J. Med. 2010, 363, 809-819
23. 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. J.; 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.; Nolop, K. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma Nature 2010, 467, 596-599
24. Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.; Faraoni, R.; Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.; Patel, H. K.; Pritchard, S.; Wodicka, L. M.; Zarrinkar, P. P. A qualitative analysis of kinase inhibitor selectivity Nat. Biotechnol. 2008, 26, 127-132
25. Fabian, M. A.; Biggs, W. H.; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lelias, J.-M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors Nat. Biotechnol. 2005, 23, 329-336 (Pubitemid 41094421)
26. Posy, S. L.; Hermsmeir, M. A.; Vaccaro, W.; Ott, K.-H.; Todderud, G.; Lippy, J. S.; Trainor, G. L.; Loughney, D. A.; Johnson, S. R. Trends in kinase selectivity: Insights for target class-focused library screening J. Med. Chem. 2011, 54, 54-66
27. Goldstein, D. M.; Gray, N. S.; Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery Nat. Rev. Drug Discovery 2008, 7, 391-397 (Pubitemid 351619111)
28. V600E inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 5342-5346
29. Abraham, S.; Bhagwat, S.; Campbell, B. T.; Chao, Q.; Faraoni, R.; Holladay, M. W.; Lai, A. G.; Rowbottom, M. W.; Setti, E.; Sprankle, K. G. Preparation of quinazoline derivatives as RAF kinase modulators for treating cancers, inflammations and immune diseases. Patent Application WO 2009117080 A1.
30. Takase, A.; Murabayashi, A.; Sumimoto, S. Practical synthesis of 3-amino-5- tert -butylisoxazole from 4,4-dimethyl-3-oxopentanenitrile with hydroxylamine Heterocycles 1991, 32, 1153-1158
31. Garteiz, D. A.; Hook, R. H.; Walker, B. J.; Okerholm, R. A. Pharmacokinetics and biotransformation studies of terfenadine in man Arzneim. Forsch. Drug Res. 1982, 32, 1185-1190 (Pubitemid 12035873)
32. Rodrigues, A. D.; Mulford, D. J.; Lee, R. D.; Surber, B. W.; Kukulka, M. J.; Ferrero, J. L.; Thomas, S. B.; Shet, M. S.; Estabrook, R. W. In vitro metabolism of terfenadine by purified recombinant fusion protein containing cytochrome P4503A4 and NADPH-P450 reductase: Comparison to human liver microsomes and precision-cut liver tissue slices Drug Metab. Dispos. 1995, 23, 765-775
33. Carlin, J. R.; Christofalo, P.; Arison, B. H.; Ellsworth, R. E.; Rosegay, A.; Miller, R. R.; Chiu, S. H. L.; Vandenheuvel, W. J. A. Disposition and metabolism of finasteride in dogs Drug Metab. Dispos. 1997, 25, 100-109 (Pubitemid 27045140)
34. Prakash, C.; Lin, J.; Colizza, K.; Miao, Z. Characterization of metabolites of a NK1 receptor antagonist, CJ-11,972, in human liver microsomes and recombinant human CYP isoforms by liquid chromatography/tandem mass spectrometry Rapid Commun. Mass Spectrom. 2007, 21, 2822-2832 (Pubitemid 47310535)
35. Park, K. B.; Kitteringham, N. R.; O'Neil, P. M. Metabolism of fluorine-containing drugs Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443-470 (Pubitemid 32385895)
36. Hodgetts, K. J.; Combs, K. J.; Elder, A. M.; Harriman, G. C. The role of fluorine in the discovery and optimization of CNS agents: Modulation of drug-like properties Annu. Rep. Med. Chem. 2010, 45, 429-448
37. Wang, Z.; Li, Y.; Liu, E. T.; Yu, Q. Susceptibility to cell death induced by blockade of MAPK pathway in human colorectal cancer cells carrying Ras mutations is dependent on p53 status Biochem. Biophys. Res. Commun. 2004, 322, 609-613 (Pubitemid 39490346)
38. Sanguinetti, M. C.; Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia Nature 2006, 440, 463-469
39. James, J.; Ruggeri, B.; Armstrong, R. C.; Rowbottom, M. W.; Jones-Bolin, S.; Gunawardane, R. N.; Dobrzanski, P.; Gardner, M. F.; Zhao, H.; Cramer, M. D.; Hunter, K.; Nepomuceno, R. R.; Cheng, M.; Gitnick, D.; Yazdanian, M.; Insko, D. E.; Ator, M. A.; Apuy, J. L.; Faraoni, R.; Dorsey, B. D.; Williams, M.; Bhagwat, S. S.; Holladay, M. W. Unpublished results.
40. Wan, P. T. C.; Garnett, M. J.; Roe, M. S.; Lee, S.; Niculescu-Duvaz, D.; Good, V. M.; Cancer Genome Project; Jones, C. M.; Marshall, C. J.; Springer, C. J.; Barford, D.; Marais, R. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF Cell 2004, 116, 855-867 (Pubitemid 38410730)
41. Weyerstahl, P.; Kressin, H.; Nerdel, F. Fragmentation reactions of carbonyl compounds with electronegative β-substituents, XV. On the reaction of electronegatively β-substituted pivalic acid esters Eur. J. Org. Chem. 1969, 725, 106-115
42. Ghose, A. K.; Herbertz, T.; Pippin, D. A.; Salvino, J. M.; Mallamo, J. P. Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery J. Med. Chem. 2008, 51, 5149-5171