Z.-F. Tao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4308–4315
4315
(b) Prudhomme, M. Recent Patents Anti-Cancer Drug
Discov. 2006, 1, 55.
7. Graves, P. R.; Yu, L.; Schwarz, J. K.; Gales, J.; Sausville,
E. A.; O’Connor, P. M.; Piwnica-Worms, H. J. Biol.
Chem. 2000, 275, 5600.
8. Jiang, X.; Zhao, B.; Britton, R.; Lim, L. Y.; Leong, D.;
Sanghera, J. S.; Zhou, B.-B. S.; Piers, S.; Andersen, R. J.;
Roberge, M. Mol. Cancer Ther. 2004, 3, 1221.
9. Curman, D.; Cinel, B.; Williams, D. E.; Rundle, N.;
Block, W. D.; Goodarzi, A. A.; Hutchins, J. R.;
Clarke, P. R.; Zhou, B.-B. S.; Lees-Miller, S. P.;
Andersen, R. J.; Roberge, M. J. Biol. Chem. 2001,
276, 17914.
10. Lyne, P. D.; Kenny, P. W.; Cosgrove, D. A.; Deng, C.;
Zabludoff, S.; Ashwell, S.; Wendoloski, J. J. J. Med.
Chem. 2004, 47, 1962.
11. Foloppe, N.; Fisher, L. M.; Howes, R.; Kierstan, P.;
Potter, A.; Robertson, A. G. S.; Surgenor, A. E. J. Med.
Chem. 2005, 48, 4332.
In summary, a new series of potent tricyclic pyrazole-
based Chk1 inhibitors are described. Analogues disub-
stituted on the 6- and 7-positions show improved
Chk1 inhibition potency compared with analogues bear-
ing a single substituent on either the 6- or 7-position.
Based on the lead compound 2, a detailed SAR study
on the 6- and 7-positions led to the identification of
the potent Chk1 inhibitors 11, 13, 16, 17, 22, 21, 23,
26, 30, 45, and 46. These compounds significantly poten-
tiate the cytotoxicity of DNA-damaging antitumor
agents in a cell-based assay and efficiently abrogate the
Dox-induced G2/M and CPT-induced S checkpoints,
supporting that their potent biological activities are
mechanism-based through Chk1 inhibition. The intro-
duction of polar groups at the 6- and 7-positions would
improve the physicochemical properties such as
solubility.
12. Lin, N.-H.; Xia, P.; Kovar, P.; Park, C.; Chen, Z.; Zhang,
H.; Rosenberg, S. H.; Sham, H. L. Bioorg. Med. Chem.
Lett. 2005, 16, 421.
Acknowledgments
13. Fraley, M. E.; Steen, J. T.; Brnardic, E. J.; Arrington, K.
L.; Spencer, K. L.; Hanney, B. A.; Kim, Y.; Hartman, G.
D.; Stirdivant, S. M.; Drakas, B. A., et al. Bioorg. Med.
Chem. Lett. 2006, 16, 6049.
14. Ni, Z.-J.; Barsanti, P.; Brammeier, N.; Diebes, A.; Poon,
D. J.; Ng, S.; Pecchi, S.; Pfister, K.; Renhowe, P. A.;
Ramurthy, S.; Wagman, A. S.; Bussiere, D. E.; Le, V.;
Zhou, Y.; Jansen, J. M.; Ma, S.; Gesner, T. G. Bioorg.
Med. Chem. Lett. 2006, 16, 3121.
The authors thank Drs. Kent D. Steward, Chang Park,
and Zhan Xiao, and Mr. Bruce Diebold for helpful
discussion.
References and notes
15. (a) Chen, Z.; Xiao, Z.; Gu, W.-Z.; Xue, J.; Bui, M.;
Kovar, P.; Li, G.; Wang, G.; Tao, Z.-F.; Tong, Y.;
Lin, N.-H.; Sham, H. L.; Wang, J. Y.; Sowin, T. J.;
Rosenberg, S. H.; Zhang, H. Y. Int. J. Cancer 2006,
2784; (b) Li, G.; Hasvold, L. A.; Tao, Z.-F.; Wang, G.
T., ; Gwaltney, S. L., II; Patel, J.; Kovar, P.; Credo,
R. B.; Chen, Z.; Zhang, H.; Park, C.; Sham, H. L.;
Sowin, T.; Rosenberg, S. H.; Lin, N. H. Bioorg. Med.
Chem. Lett. 2006, 16, 2293; (c) Wang, G. T.; Li, G.;
Mantei, R. A.; Chen, Z.; Kovar, P.; Gu, W.; Xiao, Z.;
Zhang, H.; Sham, H. L.; Sowin, T.; Rosenberg, S. H.;
Lin, N.-H. J. Med. Chem. 2005, 48, 3118.
16. Tao, Z.-F.; Wang, L.; Stewart, K. D.; Chen, Z.; Gu, W.;
Bui, M.; Merta, P.; Zhang, H.; Kovar, P.; Johnson, E.;
Park, C.; Judge, R.; Rosenberg, S.; Sowin, T.; Lin, N.-H.
J. Med. Chem. 2007, 50, 1514.
17. Tong, Y.; Claiborne, A.; Stewart, K. D.; Park, P.; Kovar,
P.; Chen, Z.; Credo, R. B.; Gu, W.-Z.; Gwaltney, S. L., II;
Judge, R. A.; Zhang, H.; Rosenberg, S. H.; Sham, H. L.;
Sowin, T. J.; Lin, N. H. Bioorg. Med. Chem. 2007, 15,
2759.
1. (a) Johnson, D. S.; Boger, D. L. Compr. Supramol. Chem.
1996, 4, 73; (b) Wolkenberg, S. E.; Boger, D. L. Chem.
Rev. 2002, 102, 2477; (c) Hurley, L. H. Nat. Rev. Cancer
2002, 2, 188; (d) Tse, W. C.; Boger, D. L. Chem. Biol.
2004, 11, 1607.
2. (a) Sancar, A.; Lindsey-Boltz, L. A.; Unsal-Kacmaz, K.;
Linn, S. Annu. Rev. Biochem. 2004, 73, 39; (b) Kastan, M.
B.; Bartek, J. Nature 2004, 432, 316.
3. (a) Chen, Y.; Sanchez, Y. DNA Repair 2004, 3, 1025; (b)
Liu, Q.; Guntuku, S.; Cui, X.; Matsuoka, S.; Cortez, D.;
Tamai, K.; Luo, G.; Carattini-Rivera, S.; DeMayo, F.;
Bradley, A.; Donehower, L. A.; Elledge, S. J. Genes Dev.
2000, 14, 1448; (c) Zhao, H.; Piwnica-Worms, H. Mol.
Cell. Biol. 2001, 21, 4129; (d) Gatei, M.; Sloper, K.;
So¨rensen, C.; Syljua¨sen, R.; Falck, J.; Hobson, K.; Savage,
K.; Lukas, J.; Zhou, B.; Bartek, J.; Khanna, K. K. J. Biol.
Chem. 2003, 278, 14806; (e) Yarden, R. I.; Pardon-Reoyo,
S.; Sgagias, M.; Cowan, K. H.; Body, L. C. Nat. Genet.
2002, 30, 285.
4. (a) Chen, Z.; Xiao, Z.; Chen, J.; Ng, S. C.; Sowin, T. J.;
Sham, H.; Rosenberg, S.; Fesik, S.; Zhang, H. Mol.
Cancer Ther. 2003, 2, 543; (b) Xiao, Z.; Chen, Z.;
Gunasekera, A. H.; Sowin, T. J.; Rosenberg, S. H.; Fesik,
S.; Zhang, H. J. Biol. Chem. 2003, 278, 21767.
18. Tricyclic pyrazole-based compounds have been reported
to inhibit other kinases, for an example, see: Doyle, J. J.;
Rafferty, P.; Steele, R. W.; Wilkins, D. J.; Arnold, L. D.;
Hockley, M.; Ericsson, A. M.; Iwasaki, N.; Ogawa, N.
WO 2001/87846.
5. Zhou, B.-B.; Bartek, J. Nat. Rev. Cancer 2004, 4, 216.
6. For recent reviews on Chk1 inhibitors, see: (a) Tao, Z.-F.;
Lin, N.-H. Anti-Cancer Agents Med. Chem. 2006, 6, 377;
19. Knight, Z. A.; Shokat, K. M. Chem. Biol. 2005, 12, 621.