S. Tasler et al. / Bioorg. Med. Chem. 17 (2009) 6728–6737
6737
16. (a) Barge, A. W.O. Patent 2004/043472 A1, 2004; Chem. Abstr. 2004, 141, 1220;
(b) Plé, P. W.O. Patent 2004/041829 A1, 2004; Chem. Abstr. 2004, 140, 423698.
17. (a) Meyer, J. F.; Wagner, E. C. J. Org. Chem. 1943, 8, 239; (b) Alexandre, F. R.;
Berecibar, A.; Besson, T. Tetrahedron Lett. 2002, 43, 3911.
18. Kolloff, H. G.; Hunter, J. H.; Woodruff, E. H.; Moffett, R. B. J. Am. Chem. Soc. 1948,
70, 3862.
were applied to cells expressing the respective RTKs. Stimulation of
cells resulted in maximal autophosphorylation in control cells (high
control) and decreased phosphorylation levels in cells bearing
successfully inhibited RTKs. Subsequently, cells were lysed using
a standard lysis buffer preserving the distinct phosphoprotein
levels. RTK-phosphorylation was quantified via sandwich ELISA
using receptor-specific capture antibodies and a phosphotyrosine
antibody.
Sigmoidal inhibitor curves based on relative inhibition com-
pared with phosphorylation levels under high control conditions
were generated and allowed the determination of EC50 values for
each test compound. For each EC50 curve, nine compound concen-
19. For similar reaction conditions (HCl, i-PrOH,
D), see: Plé, P. A.; Green, T. P.;
Hennequin, L. F.; Curwen, J.; Fennell, M.; Allen, J.; Lambert-van der Brempt, C.;
Costello, G. J. Med. Chem. 2004, 47, 871.
20. Kubo, K.; Shimizu, T.; Ohyama, S.-i.; Murooka, H.; Iwai, A.; Nakamaru, K.;
Hasegawa, K.; Kobayashi, Y.; Takahashi, N.; Takahashi, K.; Kato, S.; Izawa, T.;
Isoe, T. J. Med. Chem. 2005, 48, 1359.
21. (a) Kashiyama, E.; Hutchinson, I.; Chua, M.-S.; Stinson, S. F.; Phillips, L. R.; Kaur,
G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J. Med.
Chem. 1999, 42, 4172; (b) Hutchinson, I.; Chua, M.-S.; Browne, H. L.; Trapani, V.;
Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 2001, 44, 1446;
(c) Phoon, C. W.; Ng, P. Y.; Ting, A. E.; Yeo, S. L.; Sim, M. M. Bioorg. Med. Chem.
Lett. 2001, 11, 1647. For additional literature on 20-arylbenzothiazole
syntheses, see ref. S1, Supplementary data.
trations were measured in duplicate ranging from 1 nM to 10
as a half-logarithmic serial.
lM
22. Barbacci, E. G.; Pustilnik, L. R.; Rossi, A. M. K.; Emerson, E.; Miller, P. E.; Boscoe,
B. P.; Cox, E. D.; Iwata, K. K.; Jani, J. P.; Provoncha, K.; Kath, J. C.; Liu, Z.; Moyer, J.
Acknowledgement
D. Cancer Res. 2003, 63, 4450. Additionally,
a sequence alignment was
performed and compared with the pocket as deduced from the crystal
structure of Iressa, PDB code 2ITY.
Scientific input by Dr. Christophe Henry was highly appreciated.
23. Aronov, A. M.; McClain, B.; Moody, C. S.; Murcko, M. A. J. Med. Chem. 2008, 51,
1214.
24. Heron, N. M.; Anderson, M.; Blowers, D. P.; Breed, J.; Eden, J. M.; Green, S.; Hill,
G. B.; Johnson, T.; Jung, F. H.; McMiken, H. H. J.; Mortlock, A. A.; Pannifer, A. D.;
Pauptit, R. A.; Pink, J.; Roberts, N. J.; Rowsell, S. Bioorg. Med. Chem. Lett. 2006, 16,
1320.
25. (a) Hennequin, L. F.; Stokes, E. S. E.; Thomas, A. P.; Johnstone, C.; Plé, P. A.;
Ogilvie, D. J.; Dukes, M.; Wedge, S. R.; Kendrew, J.; Curwen, J. O. J. Med. Chem.
2002, 45, 1300; (b) Jung, F. H.; Pasquet, G.; Lambert-van der Brempt, C.;
Lohmann, J.-J. M.; Warin, N.; Renaud, F.; Germain, H.; De Savi, C.; Roberts, N.;
Johnson, T.; Dousson, C.; Hill, G. B.; Mortlock, A. A.; Heron, N.; Wilkinson, R. W.;
Wedge, S. R.; Heaton, S. P.; Odedra, R.; Keen, N. J.; Green, S.; Brown, E.;
Thompson, K.; Brightwell, S. J. Med. Chem. 2006, 49, 955; (c) Hennequin, L. F.;
Allen, J.; Breed, J.; Curwen, J.; Fennell, M.; Green, T. P.; Lambert-van der Brempt,
C.; Morgentin, R.; Norman, R. A.; Olivier, A.; Otterbein, L.; Plé, P. A.; Warin, N.;
Costello, G. J. Med. Chem. 2006, 49, 6465.
Supplementary data
Supplementary data (table with residual activities of three com-
pounds on a 252 protein kinase panel, Table S1 for quinazoline
derivatives with a solubilizing group being attached to 60-position,
and details for the synthesis of 20-(4-aminophenyl)benzothiazoles
20, 4-(benzothiazol-20-yl)phenols 21, compounds 2–9, 11–19 and
22) associated with this article can be found, in the online version,
References and notes
26. Knight, Z. A.; Shokat, K. M. Chem. Biol. 2005, 12, 621; cf. also (a) Schäfer, M.;
Egner, U. Anti-Inflamm. Anti-Allergy Agents Med. Chem. 2007, 6, 5; (b) Bain, J.;
Plater, L.; Elliott, M.; Shpiro, N.; Hastie, C. J.; McLauchlan, H.; Klevernic, I.;
Arthur, J. S. C.; Alessi, D. R.; Cohen, P. Biochem. J. 2007, 408, 297; (c) Diller, D. J.;
Li, R. J. Med. Chem. 2003, 46, 4638.
1. Tasler, S.; Müller, O.; Wieber, T.; Herz, T.; Krauss, R.; Totzke, F.; Kubbutat, M. H.
G.; Schächtele, C. Bioorg. Med. Chem. Lett. 2009, 19, 1349.
2. Harrington, E. A.; Bebbington, D.; Moore, J.; Rasmussen, R. K.; Ajose-Adeogun,
A. O.; Nakayama, T.; Graham, J. A.; Demur, C.; Hercend, T.; Diu-Hercend, A.; Su,
M.; Golec, J. M. C.; Miller, K. M. Nature Med. 2004, 10, 262.
27. Copeland, R. A.; Pompliano, D. L.; Meek, T. D. Nat. Rev. Drug Disc. 2006, 5,
730.
3. (a) Shchemelinin, I.; Sefc, L.; Necas, E. Folia Biolog. 2006, 52, 137; (b) Blume-
Jensen, P.; Hunter, T. Nature 2001, 411, 355.
28. (a) La Porta, C. A. M. Curr. Drug Targets 2004, 5, 347; (b) Sun, L.; Liang, C.;
Shirazian, S.; Zhou, Y.; Miller, T.; Cui, J.; Fukuda, J. Y.; Chu, J.-Y.; Nematalla, A.;
Wang, X.; Chen, H.; Sistla, A.; Luu, T. C.; Tang, F.; Wei, J.; Tang, C. J. Med. Chem.
2003, 46, 1116; (c) Faivre, S.; Demetri, G.; Sargent, W.; Raymond, E. Nat. Rev.
Drug Disc. 2007, 6, 734.
29. (a) Stamos, J.; Sliwkowski, M. X.; Eigenbrot, C. J. Biol. Chem. 2002, 277, 46265; (b)
Dowell, J.; Minna, J. D.; Kirkpatrick, P. Nat. Rev. Drug Disc. 2005, 4, S14.
30. (a) Gunby, R. H.; Ahmed, S.; Sottocornola, R.; Gasser, M.; Redaelli, S.; Mologni,
L.; Tartari, C. J.; Belloni, V.; Gambacorti-Passerini, C.; Scapozza, L. J. Med. Chem.
2006, 49, 5759; (b) Blencke, S.; Zech, B.; Engkvist, O.; Greff, Z.; Örfi, L.; Horvath,
Z.; Keri, G.; Ullrich, A.; Daub, H. Chem. Biol. 2004, 11, 691; (c) Böhmer, F. D.;
Karagyozov, L.; Uecker, A.; Serve, H.; Botzki, A.; Mahboobi, S.; Dove, S. J. Biol.
Chem. 2003, 278, 5148; (d) Liu, Y.; Bishop, A.; Witucki, L.; Kraybill, B.; Shimizu,
E.; Tsien, J.; Ubersax, J.; Blethrow, J.; Morgan, D. O.; Shokat, K. M. Chem. Biol.
1999, 6, 671.
4. Muhsin, M.; Graham, J.; Kirkpatrick, P. Nat. Rev. Drug Disc. 2003, 2, 515.
5. Dancey, J.; Sausville, E. A. Nat. Rev. Drug Disc. 2003, 2, 296.
6. (a) Normanno, N.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M. R.; De Luca,
A.; Caponigro, F.; Salomon, D. S. Curr. Drug Targets 2005, 6, 243; (b) Albanell, J.;
Gascon, P. Curr. Drug Targets 2005, 6, 259.
7. Blagden, S.; de Bono, J. Curr. Drug Targets 2005, 6, 325.
8. Liao, J. J.-L. J. Med. Chem. 2007, 50, 409.
9. (a) Stadler, W. M. J. Clin. Oncol. 2006, 24, 4; (b) Daub, H.; Specht, K.; Ullrich, A.
Nat. Rev. Drug Disc. 2004, 3, 1001.
10. Bridges, A. J. Chem. Rev. 2001, 101, 2541.
11. Underiner, T. L.; Ruggeri, B.; Gingrich, D. E. Curr. Med. Chem. 2004, 11, 731.
12. For a list of kinases for which binding assays have been established, see www.
proqinase.com; Sachsenmaier, C.; Schaechtele, C. BioTechniques 2002, 33, 101.
13. Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.; Barlow, J. J.; Healy, M. P.;
Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.; Henthorn, L.; Richards, L.
Bioorg. Med. Chem. Lett. 2001, 11, 1911.
14. Pandey, A.; Volkots, D. L.; Seroogy, J. M.; Rose, J. W.; Yu, J.-C.; Lambing, J. L.;
Hutchaleelaha, A.; Hollenbach, S. J.; Abe, K.; Giese, N. A.; Scarborough, R. M. J.
Med. Chem. 2002, 45, 3772.
31. Ostrander, J. H.; Daniel, A. R.; Lofgren, K.; Kleer, C. G.; Lange, C. A. Cancer Res.
2007, 67, 4199.
32. Linger, R. M. A.; Keating, A. K.; Earp, H. S.; Graham, D. K. Adv. Cancer Res. 2008,
100, 35.
33. (a) Sun, Y. Mol. Carcinog. 2006, 45, 409; (b) Macmillan, J. C.; Hudson, J. W.; Bull,
S.; Dennis, J. W.; Swallow, C. J. Ann. Surg. Oncol. 2001, 8, 729.
15. Berger, D.; Dutia, M.; Powell, D.; Wissner, A.; DeMorin, F.; Raifeld, Y.; Weber, J.;
Boschelli, F. Bioorg. Med. Chem. Lett. 2002, 12, 2989.