Discovery of a novel class of triazolones as Checkpoint Kinase inhibitors - Hit to lead exploration

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 17, 2010, Pages 5133-5138

  Oza, Vibha ^a   Ashwell, Susan ^a   Brassil, Patrick ^a   Breed, Jason ^a   Deng, Chun ^a   Ezhuthachan, Jay ^a   Haye, Heather ^a   Horn, Candice ^a,b   Janetka, James ^a,c   Lyne, Paul ^a   Newcombe, Nicholas ^a   Otterbien, Ludo ^a   Pass, Martin ^a   Read, Jon ^a   Roswell, Sian ^a   Su, Mei ^a   Toader, Dorin ^a   Yu, Dingwei ^a   Yu, Yan ^a   Valentine, Anna ^a   Webborn, Peter ^a   White, Ann ^a   Zabludoff, Sonya ^a,d   Zheng, Xiaolan ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b Lilly   (United States)

^c WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d PFIZER INC   (United States)

Author keywords

Checkpoint Kinase inhibitors; CHK1; Triazolones

Indexed keywords

4 METHYL 7 TRIAZOLONE DERIVATIVE; CHECKPOINT KINASE 1; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DNA DAMAGE; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG STRUCTURE; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; STRUCTURE ACTIVITY RELATION;

CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; MODELS, MOLECULAR; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

EID: 77955653997     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.07.015     Document Type: Article

References (29)

1. N. Bucher, and C.D. Britten Br. J. Cancer 98 2008 523
2. Y. Luo, and J.D. Leverson Expert Rev. Anticancer Ther. 5 2005 333 and references cited within
3. Enzyme and cellular assays have been described in detail in a prior publication as referenced in 13
4. S. Zabludoff, C. Deng, M. Grondine, A. Sheehy, S. Ashwell, B. Caleb, S. Green, H. Haye, C. Horn, J. Janetka, D. Liu, E. Mouchet, S. Ready, J. Rosenthal, C. Queva, G.K. Schwartz, K.J. Taylor, A.N. Tse, G.E. Walker, and A.M. White Mol. Cancer Ther. 7 2008 9
5. J.W. Janetka, S. Ashwell, S. Zabludoff, and P. Lyne Curr. Opin. Drug Discovery Dev. 10 2007 473
6. K.L. Arrington, and V.Y. Dudkin ChemMedChem 2 2007 1571
7. Z.-F. Tao, and N.-H. Lin Anticancer Agents Med. Chem. 6 2006 377
8. M. Prudhomme Recent Patents Anti-Cancer Drug Discovery 11 2006 55
9. Q. Wang, S. Fan, A. Eastman, P. Worland, E. Sausville, and P. O'Connor J. Natl. Cancer Inst. 88 1996 956
10. P. Graves, L. Yu, and J. Schearz J. Biol. Chem. 275 2000 5600
11. E. Busby, D. Leistritz, R. Abraham, L. Karnitz, and J. Sarkaria Cancer Res. 60 2000 2108
12. C. Fernanda, and W. Filgueira de Azevido Jr. Curr. Comput. Aided Drug Des. 1 2005 53
13. D. Komander, G. Kular, J. Bain, M. Elliot, and D. Van Aalten Biochem. J. 375 2003 255
14. P. Goekjian, and M. Jirousek Expert Opin. Invest. Drugs 10 2001 2117
15. J. Janetka, L. Almeida, S. Ashwell, P. Brassil, K. Daly, C. Deng, T. Gero, R. Glynn, C. Horn, S. Ioannidis, P. Lyne, N. Newcombe, V. Oza, M. Pass, S. Springer, M. Su, D. Toader, M. Vasbinder, D. Yu, Y. Yu, and S. Zabludoff Bioorg. Med.Chem. Lett. 18 2008 4242
16. The Dundee screen was carried out at 10 μM of compound 3, 5-50 μM of ATP and consisted of 25 kinases.
17. 20 and structure factors for the CHK complexes with compounds 3, 4a, and 28 have been deposited in the Protein Data Bank (2x8d, 28xi, and 2x8e, respectively) together with structure factors and detailed experimental conditions.
18. Unpublished data.
19. S. Davis, B. Rauckman, J. Chan, and B. Roth J. Med. Chem. 32 1989 1936
20. C6 positional isomers of compounds 20 and 26 were 2.5 and 1.8 μM, respectively.
21. S. Ashwell, J. Janetka, and S. Zabludoff Expert Opin. Invest. Drugs 17 2008 1331
22. W.L. DeLano The PyMOL Molecular Graphics System 2002 DeLano Scientific San Carlos, CA, USA http://www.pymol.org
23. CCP4, Acta Crystallogr., Sect. D 1994, 50, 760-763.
24. QUANTA2000, Accelrys.
25. A. Coot, P. Emsley, and K. Cowtan Acta Crystallogr., Sect. D 60 2004 2126
26. Flynn, version 1.1.1, OpenEye Scientific Software, Inc., Santa Fe, NM, USA, www.eyesopen.com, 2010.
27. CNX Version 2000.1, Accelrys.
28. Refmac version 5.1.17 G.N. Murshudov, A.A. Vagin, and E.J. Dodson Acta Crystallogr., Sect. D 53 1997 240
29. 2, respectively.