Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-74057 DMSO solvate)

ACS Medicinal Chemistry Letters

Volumn 2, Issue 4, 2011, Pages 320-324

  Abe, Hiroyuki ^a   Kikuchi, Shinichi ^a   Hayakawa, Kazuhide ^a   Iida, Tetsuya ^a   Nagahashi, Noboru ^a   Maeda, Katsuya ^a   Sakamoto, Johei ^a   Matsumoto, Noriaki ^a   Miura, Tomoya ^a   Matsumura, Koji ^a   Seki, Noriyoshi ^a   Inaba, Takashi ^a   Kawasaki, Hisashi ^a   Yamaguchi, Takayuki ^a   Kakefuda, Reina ^a   Nanayama, Toyomichi ^a   Kurachi, Hironori ^a   Hori, Yoshikazu ^a   Yoshida, Takayuki ^b   Kakegawa, Junya ^b   Watanabe, Yoshihiro ^b   Gilmartin, Aidan G ^c   Richter, Mark C ^c   Moss, Katherine G ^c   Laquerre, Sylvie G ^c   more..

^a Central Pharmaceutical Research Institute   (Japan)

^b Pharmaceutical Frontier Research Laboratory   (Japan)

^c GLAXOSMITHKLINE   (United States)

Author keywords

antiproliferative; GSK1120212; JTP 74057; MEK inhibitor

Indexed keywords

GSK 1120212; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; N {3 [3 CYCLOPROPYL 5 (2 FLUORO 4 IODOPHENYLAMINO) 6,8 DIMETHYL 2,4,7 TRIOXO 3,4,6,7 TETRAHYDRO 2H PYRIDO[4,3 D]PYRIMIDIN 1 YL]PHENYL}ACETAMIDE DIMETHYLSULFOXIDE SOLVATE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CANCER CELL; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG POTENCY; DRUG SELECTIVITY; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT;

EID: 79954576977     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml200004g     Document Type: Article

References (16)

1. Sebolt-Leopold, J. S.; Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer Nat. Rev. Cancer 2004, 4, 937-947 (Pubitemid 39626217)
2. McCubrey, J. A.; Milella, M.; Tafuri, A.; Martelli, A. M.; Lunghi, P.; Bonati, A.; Cervello, M.; Lee, J. T.; Steelman, L. S. Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors Curr. Opin. Invest. Drugs 2008, 9, 614-630 (Pubitemid 351777165)
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, 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.; 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)
4. Adjei, A. A. Blocking oncogenic Ras signaling for cancer therapy J. Natl. Cancer Inst. 2001, 93, 1062-1074 (Pubitemid 32717538)
5. Porter, A. C.; Vaillancourt, R. R. Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis Oncogene 1998, 17, 1343-1352 (Pubitemid 28458404)
6. Frémin, C.; Meloche, S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy J. Hematol. Oncol. 2010, 3, 8
7. INK4b-inductive compound, as a novel MEK1/2 inhibitor Cancer Sci. 2007, 98, 1809-1816 (Pubitemid 47487919)
8. Yoshida, T.; Unpublished results.
9. Sakai, T.; Kawasaki, H.; Abe, H.; Hayakawa, K.; Iida, T.; Kikuchi, S.; Yamaguchi, T.; Nanayama, T.; Kurachi, H.; Tamaru, M.; Hori, Y.; Takahashi, M.; Yoshida, T. 5-Amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2 H -pyrido-[2,3- d ]-pyrimidine derivatives and related compounds for the treatment of cancer. WO-2005121142, 2005.
10. Gilmartin, A. G.; Bleam, M. R.; Groy, A.; Moss, K. G.; Minthorn, E. A.; Kulkarni, S. G.; Rominger, C. M.; Erskine, S; Fisher, K. E.; Yang, J.; Zappacosta, F.; Annan, R.; Sutton, D.; Laquerre, S. G. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin. Cancer Res., published online January 18, 2011; DOI: 10.1158/1078-0432.
11. The specificity of GSK1120212 for MEK1/2 was confirmed against a panel of >180 kinases including B-Raf, C-RAf, and MEK5, the closest kinase homologue. See ref 10 and Yamaguchi, T.; Unpublished results.
12. Barrett, S. D.; Bridges, A. J.; Dudley, D. T.; Saltiel, A. R.; Fergus, J. H.; Flamme, C. M.; Delaney, A. M.; Kaufman, M.; LePage, S.; Leopold, W. R.; Przybranowski, S. A.; Sebolt-Leopold, J.; Van Becelaere, K; Doherty, A. M.; Kennedy, R. M.; Marston, D.; Howard, W. A., Jr.; Smith, Y.; Warmus, J. S.; Tecle, H. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901 Bioorg. Med. Chem. Lett. 2008, 18, 6501-6504
13. Wallace, E.; Yang, H. W.; Lyssikatos, J. P. Bicyclic inhibitors of MEK and methods of use thereof. WO-05051300, 2004.
14. Spicer, J. A.; Rewcastle, G. W.; Kaufman, M. D.; Black, S. L.; Plummer, M. S.; Denny, W. A.; Quin, J., III; Shahripour, A. B.; Barrett, S. D.; Whitehead, C. E.; Milbank, J. B. J.; Ohren, J. F.; Gowan, R. C.; Omer, C.; Camp, H. S.; Esmaeil, N; Moore, K.; Sebolt-Leopold, J. S.; Pryzbranowski, S.; Merriman, R. L.; Ortwine, D. F.; Warmus, J. S.; Flamme, C. M.; Pavlovsky, A. G.; Tecle, H. 4-Anilino-5-carboxamido-2-pyridone Derivatives as Noncompetitive Inhibitors of Mitogen-Activated Protein Kinase Kinase J. Med. Chem. 2007, 50, 5090-5102 (Pubitemid 47585706)
15. Wallace, E. M.; Lyssikatos, J.; Blake, J. F.; Seo, J.; Yang, H. W.; Yeh, T. C.; Perrier, M.; Jarski, H.; Marsh, V.; Poch, G.; Livingston, M. G.; Otten, J.; Hingorani, G.; Woessner, R.; Lee, P.; Winkler, J.; Koch, K. Potent and Selective Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors. 1. 4-(4-Bromo-2-fluorophenylamino)-1-methylpyridin-2(1 H)-ones J. Med. Chem. 2006, 49, 441-444 (Pubitemid 43157473)
16. In ref 14, it was pointed out that N- Me pyridones are active in the kinase and cellular assays, but N- H pyridones are not potent. They speculated that the drop of activity of N- H pyridones may be attributed to the loss of the key hydrogen bond to Ser212 due to partial tautomerization of the pyridone system. However, in our case, introduction of a methyl group in the corresponding position, that is, 6 to 7, does not change the tautomerization state of the pyrido[4,3- d ]pyrimidine core, so we speculated that methyl group affected the orientation of neighboring phenyl ring.