Novel potent BRAF inhibitors: Toward 1 nM compounds through optimization of the central phenyl ring

Journal of Medicinal Chemistry

Volumn 52, Issue 13, 2009, Pages 3881-3891

  Ménard, Delphine ^a   Niculescu Duvaz, Ion ^a   Dijkstra, Harmen P ^a   Niculescu Duvaz, Dan ^a   Suijkerbuijk, Bart M J M ^a   Zambon, Alfonso ^a   Nourry, Arnaud ^a   Roman, Esteban ^a   Davies, Lawrence ^a   Manne, Helen A ^a   Friedlos, Frank ^a   Kirk, Ruth ^a   Whittaker, Steven ^a   Gill, Adrian ^b   Taylor, Richard D ^b   Marais, Richard ^a   Springer, Caroline J ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b ASTEX PHARMACEUTICALS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 (2,3 DIHYDRO 2 OXO 1H IMIDAZO[4,5 B]PYRIDIN 7 YLOXY) 2 METHYLTHIOPHENYL] 3 [4 CHLORO 3 (TRIFLUOROMETHYL)PHENYL]UREA; 1 [4 (2,3 DIHYDRO 2 OXO 1H IMIDAZO[4,5 B]PYRIDIN 7 YLOXY) 3 METHOXYPHENYL] 3 [4 CHLORO 3 (TRIFLUOROMETHYL)PHENYL]UREA; 1 [4 CHLORO 3 (TRIFLUOROMETHYL)PHENYL] 3 [2 METHYLSULFONYL 4 (2 OXO 2,3 DIHYDRO 1H IMIDAZO[4,5 B]PYRIDIN 7 YLOXY)PHENYL]UREA; 1H IMIDAZO[4,5 B]PYRIDINE 2(3H) ONE; B RAF KINASE; N [4 (2 OXO 2,3 DIHYDRO 1H IMIDAZO[4,5 B]PYRIDIN 7 YL OXY)NAPHTHALEN 1 YL]AMINOCARBONYLMETHYLENE 3 TRIFLUOROMETHYLPHENYL; PROTEIN SERINE THREONINE KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING SITE; CONTROLLED STUDY; DRUG MECHANISM; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME ACTIVITY; HUMAN; HUMAN CELL; IC 50; MELANOMA CELL; SIGNAL TRANSDUCTION; SUBSTITUTION REACTION;

ALLOSTERIC SITE; ANTINEOPLASTIC AGENTS; INHIBITORY CONCENTRATION 50; MELANOMA; MUTATION, MISSENSE; PHENOLS; PROTO-ONCOGENE PROTEINS B-RAF; PYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 67649992844     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900242c     Document Type: Article

References (28)

1. Robinson, M. J.; Cobb, M. H. Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 1997, 9, 180-186.
2. Cohen, P. Protein kinasessthe major drug targets of the twenty-first century. Nat. Rev. Drug Discovery 2002, 1, 309-315.
3. 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, N.; 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.; Siegler, 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.
4. Wan, P. T. C.; 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.; Marais, R.; Cancer Genome, P. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004, 116, 855-867.
5. 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.; Marais, R. B-RAF is a therapeutic target in melanoma. Oncogene 2004, 23, 6292-6298.
6. Friday, B. B.; Adjei, A. A. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin. Cancer Res. 2008, 14, 342-346.
7. Brown, A. P.; Carlson, T. C. G.; Loi, C. M.; Graziano, M. J. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother. Pharmacol. 2007, 59, 671-679.
8. Davies, B. R.; Logie, A.; McKay, J. S.; Martin, P.; Steele, S.; Jenkins, R.; Cockerill, M.; Cartlidge, S.; Smith, P. D. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/ pharmacodynamic relationship, and potential for combination in preclinical models. Mol. Cancer Ther. 2007, 6, 2209-2219.
9. Sala, E.; Mologni, L.; Truffa, S.; Gaetano, C.; Bollag, G. E.; 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. 2008, 6, 751-759.
10. 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.
11. Sebolt-Leopold, J. S.; Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat. Rev. Cancer 2004, 4, 937-947.
12. Adjei, A. A.; Cohen, R. B.; Franklin, W.; Morris, C.; Wilson, D.; Molina, J. R.; Hanson, L. J.; Gore, L.; Chow, L.; Leong, S.; Maloney, L.; Gordon, G.; Simmons, H.; Marlow, A.; Litwiler, K.; Brown, S.; Poch, G.; Kane, K.; Haney, J.; Eckhardt, S. G. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J. Clin. Oncol. 2008, 26, 2139-2146.
13. Niculescu-Duvaz, I.; Roman, E.; Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I. J.; Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer, C. J. Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead. J. Med. Chem. 2006, 49, 407-416.
14. Niculescu-Duvaz, I.; Roman, E.; Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I. J.; Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer, C. J. Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold. J. Med. Chem. 2008, 51, 3261-3274.
15. Niculescu-Duvaz, D.; Gaulon, C.; Dijkstra, H. P.; Niculescu-Duvaz, I.; Zambon, A.; Ménard, D.; Suijkerbuijk, B. M. J. M.; Nourry, A.; Davies, L.; Manne, H.; Friedlos, F.; Ogilvie, L.; Hedley, D.; Whittaker, S.; Kirk, R.; Gill, A.; Taylor, R. D.; Raynaud, F. I.; Moreno-Farre, J.; Marais, R.; Springer, C. J. Pyridoimidazolones as Novel Potent Inhibitors of v-Raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF). J. Med. Chem. 2009, 52, 2255-2264.
16. Liao, J. J. L. Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem. 2007, 50, 409-424.
17. Cervera, M.; Marquet, J.; Martin, X. Charge control in the SNAr reaction. Meta substitution with respect to the activating nitro group in 3,4-dihalogenonitrobenzenes. Tetrahedron 1996, 52, 2557-2564.
18. Langer, O.; Dolle, F.; Valette, H.; Halldin, C.; Vaufrey, F.; Fuseau, C.; Coulon, C.; Ottaviani, M.; Nagren, K.; Bottlaender, M.; Maziere, B.; Crouzel, C. Synthesis of high-specific-radioactivity 4- and 6-[F-18]fluorometaraminol-PET tracers for the adrenergic nervous system of the heart. Bioorg. Med. Chem. 2001, 9, 677-694.
19. Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M. New efficient synthesis of 4-amino-3-arylphenols. Synthesis Stuttgart 1995, 671-674.
20. Winn, M.; Reilly, E. B.; Liu, G.; Huth, J. R.; Jae, H. S.; Freeman, J.; Pei, Z. H.; Xin, Z. L.; Lynch, J.; Kester, J.; von Geldern, T. W.; Leitza, S.; DeVries, P.; Dickinson, R.; Mussatto, D.; Okasinski, G. F. Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationship of substituents on the benzene ring of the cinnamide. J. Med. Chem. 2001, 44, 4393-4403.
21. Kundu, N. G.; Nandi, B. Palladium-copper catalyzed synthesis of benzofused heterocycles with two heteroatoms: Novel and highly regio- and stereoselective syntheses of (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3- benzothiazoles and (E)-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4- benzothiazines. J. Org. Chem. 2001, 66, 4563-4575.
22. Chankeshwara, S. V.; Chakraborti, A. K. Indium(III) halides as new and highly efficient catalysts for N-tert-butoxycarbonylation of amines. Synthesis 2006, 2784-2788.
23. The phospho-ERK method is included in the Supporting Information.
24. TSARTM 3.3; Oxford Molecular Limited: Oxford, UK, 2000.
25. Filippakopoulos, P., Barr, A., Fedorov, O., Keates, T., Soundararajan, M., Elkins, J., Salah, E., Burgess-Brown, N., Ugochukwu, E., Pike, A. C. W., Muniz, J., Roos, A., Chaikuad, A., von Delft, F., Arrowsmith, C. H., Edwards, A. M., Weigelt, J., Bountra, C., Knapp, S. Crystal Structure of Human Mitogen Activated Protein Kinase 11 (p38 beta) in complex with Nilotinib. Structural Genomics Consortium (SGC) 2009; to be published.
26. Seeliger, M. A.; Nagar, B.; Frank, F.; Cao, X.; Henderson, M. N.; Kuriyan, J. c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure 2007, 15, 299-311.
27. Jacobs, M. D.; Caron, P. R.; Hare, B. J. Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: Structure of lck/imatinib complex. Proteins: Struct., Funct., Bioinf. 2008, 70, 1451-1460.
28. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol. 2002, 9, 268-272.