3492
B. J. Newhouse et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3488–3492
Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.;
9. (a) Tautomer preferences were computed using the 6-31G(d) basis set. Frisch,
M. J. et al. GAUSSIAN98, Revision A.11, Gaussian: Pittsburgh, PA.; (b) Free energies
of solvation were calculated using SM2.1 Amsol 5.0: Cramer, C. J.; Hawkins, G.
D.; Lynch, G. C.; Giesen, D. J.; Rossi, I; Storer, J. W.; Truhlar, D. G.; Liotard, D. A.
In AMSOL-version 5.0, Quantum Chemistry Program Exchange Program 606, based
in part on AMPAC-version 2.1, Liotard, D. A.; Healy, E. F.; Ruiz, J. M.; Dewar, M. J.
S.
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. Nature 2002, 417, 949–954; (b) Cohen,
Y.; Xing, M.; Mambo, E.; Guo, Z.; Wu, G.; Trink, B.; Beller, U.; Westra, W. H.;
Ladenson, P. W.; Sidransky, D. J. Natl. Cancer Inst. 2003, 95(8), 625–627; (c) Xu,
X.; Quiros, R. M.; Gattuso, P.; Ain, K. B.; Prinz, R. A. Cancer Res. 2003, 63(15),
4561–4567.
10. For assay description see: Laird, E.; Lyssikatos, J.; Welch, M.; Grina, J.; Hansen,
J.; Newhouse, B.; Olivero, A.; Topolav, G. WO 2006/084015 A2, 2006.
11. Computed relative energies for the two pyrazole tautomers indicates
a
3. (a) Kalinsky, K.; Haluska, F. G. Expert Rev. Anticancer Ther. 2007, 7, 715–724; (b)
Dhillon, D. S.; Hagan, S.; Rath, O.; Kolch, W. Oncogene 2007, 26, 3279–3290.
4. Wan, P. T.; Garnet, 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. Cell 2004, 116,
855–867.
significant population of the undesired tautomer also exists (data not shown).
12. Ren, L.; Wenglowsky, S.; Miknis, G.; Rast, B.; Buckmelter, A. J.; Ely, R. J.;
Schlachter, S.; Laird, E. R.; Randolph, N.; Callejo, M.; Martinson, M.; Galbraith,
S.; Brandhuber, B. J.; Vigers, G.; Morales, T.; Voegtli, W.; Lyssikatos, J. Bioorg
Med. Chem. Lett. 2011, 21, 1243–1247.
5. McCubrey, J. A.; Milella, M.; Tafuri, A.; Martelli, A. M.; Lunghi, P.; Bonai, A.;
Cervello, M.; Lee, J. T.; Steelman, L. S. Curr. Opin. Invest. Drugs 2008, 9, 614–630.
6. Hansen, J. D.; Grina, J.; Newhouse, B.; Welch, M.; Topalov, G.; Littman, N.;
Callejo, M.; Gloor, S.; Martinson, M.; Laird, E.; Brandhuber, B. J.; Vigers, G.;
Morales, T.; Woessner, R.; Randolph, N.; Lyssikatos, J.; Olivero, A. Bioorg. Med.
Chem. Lett. 2008, 18, 4692–4695.
7. (a) Choo, E. F.; Driscoll, J. P.; Feng, J.; Liederer, B.; Plise, E.; Randolph, N.; Shin, Y.;
Wong, S.; Ran, Y. Xenobiotica 2009, 39(09), 700–709; (b) Coutts, R. T.; Dawe, R.;
Dawson, G. W.; Kovach, S. H. Drug Metab. Disp. 1976, 4, 35–39; (c) Heberling, S.;
Girreser, U.; Wolf, S.; Clement, B. Biochem. Pharmacol. 2006, 71, 354–365.
8. PDB accession code 3D4Q.
13. Tao, Z.-F.; Sowin, T.; Lin, N.-H. Tetrahedron Lett. 2005, 46, 7615–7618.
14. (a) Hagmann, W. J. Med. Chem. 2008, 51, 4359–4369; (b) Bohm, H.-J.; Banner,
D.; Bendels, S.; Kansay, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637–643; (c) van Niel, M. B.; Collins, I.; Beer, M. S.;
Broughton, H. B.; Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.;
MacLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.;
Russell, M. G. N.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.;
Castro, J. J. Med. Chem. 1999, 42, 2087–2104.
15. Determined by 1H NMR.
16. Shellhamer, D. F.; Briggs, A. A.; Miller, B. M.; Prince, J. M.; Scott, D. H.; Heasley,
V. L. J. Chem. Soc., Perkin Trans. 2 1996, 973–977.