Browse > Article

Topomer-CoMFA Study of Tricyclic Azepine Derivatives-EGFR Inhibitors  

Chung, Jae-Yoon (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Pasha, F.A. (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Chung, Hwan-Won (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Yang, Beom-Seok (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Lee, Cheol-Ju (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Oh, Jung-Soo (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Moon, Myoung-Woon (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Cho, Seung-Joo (Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology)
Cho, Art E. (Department of Biotechnology and Bioinformatics, Korea University)
Publication Information
Molecular & Cellular Toxicology / v.4, no.1, 2008 , pp. 78-84 More about this Journal
Abstract
EGFR has been intensively investigated as a target to block the signal transduction pathway which stimulates cancer growth and metastasis. Studies about structure-activity relationship for tricyclic azepine derivatives were performed with topomer-CoMFA. The derived topomer-CoMFA model with steric and electrostatic field parameters based on fragment units gave reasonable statistics ($q^2$=0.561, $r^2$=0.679). The model explains why a halogen atom at the meta position of aniline is important to increases inhibitory activity. This comes from an electrostatically negative groups are favored near this region. The model also shows that there are sterically favored regions around methoxy group extended from oxazepine derivatives. The findings about steric and electrostatic effects can be utilized for designing new inhibitors.
Keywords
Topomer-CoMFA; EGFR; QSAR;
Citations & Related Records

Times Cited By Web Of Science : 1  (Related Records In Web of Science)
연도 인용수 순위
  • Reference
1 Sorrentino, B. P. Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs. Nat Rev Cancer 2:431-441 (2002)   DOI   ScienceOn
2 Hubbard, S. R. & Till, J. H. Protein tyrosine kinase structure and function. Annual Review of Biochemistry 69:373-398 (2000)   DOI   ScienceOn
3 Janmaat, M. L. & Giaccone, G. Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist 8:576-586 (2003)   DOI
4 Traxler, P. et al. Tyrosine kinase inhibitors: from rational design to clinical trials. Medicinal Research Reviews 21:499-512 (2001)   DOI   ScienceOn
5 Stamos, J., Sliwkowski, M. X. & Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 277:46265-46272 (2002)   DOI   ScienceOn
6 Cramer, R. D. & Patterson, D. E. Further method of creating and rapidly searching a virtual library of potential molecules using validated molecular structural descriptors. United States. (2001)
7 Baselga, J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 7:2-8 (2002)
8 Lo, H-W., Hsu, S. C. & Hung, M. C. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Research and Treatment 95:211-218 (2006)   DOI
9 Wold, S., Sjostrom, M. & Eriksson, L. PLS-regression: a basic tool of chemometrics. Chemometrics and Intelligent Laboratory Systems 58:109-130 (2001)   DOI   ScienceOn
10 Toschi, L. & Cappuzzo, F. Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist 12:211-220 (2007)   DOI   ScienceOn
11 Smith Ii, L. et al. Novel tricyclic azepine derivatives: biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase. Bioorganic & Medicinal Chemistry Letters 16:5102-5106 (2006)   DOI   ScienceOn
12 Cohen, P. Protein kinases-the major drug targets of the twenty-first century? Nature Reviews Drug Discovery 1:309-315 (2002)   DOI   ScienceOn
13 Cramer, R. D. Topomer CoMFA: A design methodology for rapid lead optimization. J Med Chem 46:374-388 (2003)   DOI   ScienceOn
14 Tripos Bookshelf 7.3. Tripos Inc. (1699)
15 Noble, M. E. M., Endicott, J. A. & Johnson, L. N. Protein kinase inhibitors: insights into drug design from structure. Sience 303:1800-1805 (2004)   DOI
16 Cramer, R. D. & Jilek, R. J. Comparative field analysis (CoMFA) utilizing topomeric alignment of molecular fragments. United States. (2003)
17 Bush, B. L. & Nachbar, R. B. Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA. Journal of Computer-Aided Molecular Design 7:587-619 (1993)   DOI
18 Kurup, A., Garg, R. & Hansch, C. Comparative QSAR study of tyrosine kinase inhibitors. Chem Rev 101:2573-2600 (2001)   DOI   ScienceOn
19 Dawson, J. P. et al. Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol Cell Biol 25:7734-7742 (2005)   DOI   ScienceOn
20 Bridges, A. J. et al. Tyrosine kinase inhibitors. 8. an unusually steep structure-activity relationship for analogues of 4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem 39:267-276 (1996)   DOI   ScienceOn
21 Jilek, R. J. & Cramer, R. D. Topomers: a validated protocol for their self-consistent generation. J Chem Inf Comput Sci 44:1221-1227 (2004)   DOI   ScienceOn
22 Katsman, A., Umezawa, K. & Bonavida, B. Reversal of resistance to cytotoxic cancer therapies: DHMEQ as a chemo-sensitizing and immuno-sensitizing agent. Drug Resistance Updates 10:1-12 (2007)   DOI   ScienceOn