1318
Q. Dong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1315–1319
Marston, D.; Howard, W. A.; Smith, Y.; Warmus, J. S.; Tecle, H. Bioorg. Med.
Table 4
Selected PK parameters for compound 17 (TAK-733)21
Chem. Lett. 2008, 18, 6501; (b) Sebolt-Leopold, J. S.; Bridges, A. J. Kinase Inhibitor
Drugs 2009, 205.
5. (a) Wallace, E. M.; Lyssikatos, J. P.; Yeh, T.; Winkler, J. D.; Koch, K. Curr. Top. Med.
Chem. 2005, 5, 215; (b) Wallace, E. M.; Blake, J. F. Kinase Inhibitor Drugs 2009,
229.
Species
CL (mL/min/kg) Vdss (mL/kg) MRTiv (h) MRTpo (h) F (%)
Mouse
Rat
Dog
17.2
13.7
5.9
1955
1643
3070
3745
1.9
2.0
8.9
5.8
4.6
11.5
12.9
23.8
67
71
6. (a) Rosen, L. S.; Galatin, P.; Fehling, J. M.; Laux, I.; Dinolfo, M.; Frye, J.; Laird, D.;
Sikic, B. I. ASCO Annual Meeting Abstract 14585, 2008.; (b) Iverson, C.; Larson,
G.; Lai, C.; Yeh, L.-T.; Dadson, C.; Weingarten, P.; Appleby, T.; Vo, T.; Maderna,
A.; Vernier, J.-M.; Hamatake, R.; Miner, J. N.; Quart, B. Cancer Res. 2009, 69,
6839; (c) Tai, Y.-T.; Kim, K.; Li, X.-F.; Fulciniti, M.; Song, W.; Nahar, S.; Burger,
P.; Rumizen, M. J.; Podar, K.; Chauhan, D.; Hideshima, T.; Schlossman, R. L.;
Munshi, N. C.; Richardson, P.; Clark, A.; Ogden, J.; Andreas, G.; Rastelli, L.;
Anderson, K. C. ASH Annual Meeting and Exposition Abstract 3848, 2009.; (d)
Wallace, E. M.; Lyssikatos, J.; Blake, J. F.; Marlow, A.; Greschuk, J.; Yeh, T. C.;
Callejo, M.; Marsh, V.; Poch, G.; Otten, J.; Hingorani, G.; Winski, S. L.; Anderson,
D. A.; Lee, P.; Winkler, J.; Koch, K.; Davies, B. R.; Jones, D. C.; Logie, A.; Curtis, N.
J.; Chresta, C. M.; Smith, P. D.; Robinson, D. T. AACR Abstract 3696, 2009.; (e)
Lee, L.; Niu, H.; Rueger, R.; Igawa, Y.; Deutsch, J.; Ishii, N.; Mu, S.; Sakamoto, Y.;
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McConnell, P.; Spessard, C.; Banotai, C.; Mueller, W. T.; Delaney, A.; Omer, C.;
Sebolt-Leopold, J.; Dudley, D. T.; Leung, I. K.; Flamme, C.; Warmus, J.; Kaufman,
M.; Barrett, S.; Tecle, H.; Hasemann, C. A. Nat. Struct. Mol. Biol. 2004, 12, 1192.
8. Molecular Operating Environment (MOE), Chemical Computing Group Inc.,
76
Monkey 11.1
>3822
The pharmacokinetics of TAK-733 was evaluated in nude
mouse, rat, dog and monkey (Table 4). Low clearance and high oral
bioavailability were observed in all species. TAK-733 demonstrated
broad antitumor activity in mouse xenograft models of human
cancer including models of melanoma, colorectal, NSCLC, pancre-
atic and breast cancer. Further detailed in vivo data will be pre-
sented in future publications.
In summary, we have discovered a series of potent, selective,
ATP-noncompetitive MEK inhibitors. TAK-733 has demonstrated
potent anticancer activity in several mouse xenograft models. It
is well tolerated with pharmacokinetics and pharmacodynamics
that support once-daily oral dosing in humans. Based on its potent
antitumor activities and its safety profiles, TAK-733 was advanced
to Phase I clinical studies for cancer treatment.
9. (a) Kawasaki, H.; Abe, H.; Hayakawa, K.; Iida, T.; Kikuchi, S.; Yamaguchi, T.;
Nanayama, T.; Kurachi, H.; Tamaru, M.; Hori, Y.; Takahashi, M.; Yoshida, T. PCT
Int. Patent Appl. WO 05/121142, 2005.; (b) Wallace, E. Yang, H. W.; Lyssikatos,
J. P. PCT Int. Patent Appl. WO 05/051300, 2005.
10. (a) Spicer, J. A.; Rewcastle, G. W.; Kaufman, M. D.; Black, S. L.; Plummer, M. S.;
Denny, W. A.; Quin, J.; 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. J. Med. Chem. 2007,
50, 5090; (b) 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.;
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441.
11. (a) Barrett, S. D.; Bridges, A. J.; Flamme, C. M.; Kaufam, M.; Doherty, A. M.;
Kennedy, R. M.; Marston, D.; Howard, W. A.; Smith, Y.; Warmus, J. S.; Tecle, H.;
Dudley, D. T.; Saltiel, A. R.; Fergus, J. H.; Delaney, A. M.; Lepage, S.; Leopold, W.
R.; Przybranowski, S. A.; Sebolt-Leopold, J.; Van Becelaere, K. Bioorg. Med. Chem.
Lett. 2008, 18, 6501; (b) Warmus, J. S.; Flamme, C.; Zhang, L. Y.; Barrrett, S.;
Bridges, A.; Kaufman, M.; Tecle, H.; Gowan, R.; Sebolt-Leopold, J.; Leopold, W.;
Merriman, R.; Przybranowski, S.; Valik, H.; Chen, J.; Ohren, J.; Pavlovsky, A.;
Whithead, C.; Ahang, E. Bioorg. Med. Chem. Lett. 2008, 18, 6171.
12. Full experimental procedures for compounds 1–27 are contained within the
following patent application: Dong, Q.; Gong, X.; Kaldor, S. W.; Kanouni, T.;
Scorah, N.; Wallace, M. B.; Zhou, F. PCT Int. Patent Appl. WO 08/079814.
13. MEK1 enzyme assay: Inhibition of compounds relative to MEK1 were
determined using a cascade assay method in 384 well format under the
following reaction conditions: test compounds serial diluted in DMSO were
diluted into assay buffer (50 mM HEPES pH 7.3, 10 mM NaCl, 10 mM MgCl2,
0.01% Brij35, 1 mM DTT) and added into ERK1, fluorescent labeled ERK1
substrate: IPTTPITTYFFFK-5FAM-COOH, and the reaction was initiated with
Acknowledgements
The authors thank the following scientists for their valuable
experimental assistance: Lilly Zhang (DMPK), Melinda Manuel
(DMPK), Victoria Feher (Computational Chemistry), Bi-Ching Sang
(cloning), and Gyorgy Snell (crystallography data collection). We
thank Keith Wilson and Patrick Vincent for project leadership,
and Andy Jennings for technical assistance in Computational
Chemistry. The X-ray crystallography data reported here is based
on research conducted at the Advanced Light Source (ALS) using
beam line ALS 5.0.2. ALS is supported by the Director, Office of Sci-
ence, Office of Basic Energy Sciences, Materials Sciences Division, of
the U.S. Department of Energy (DOE) under Contract No. DE-AC02-
05CH11231 at Lawrence Berkeley National Laboratory. We thank
the staff at ALS for their support in the use of the synchrotron beam
lines.
References and notes
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