Discovery of HER2/neu Tyrosine Kinase Inhibitor through Computer-Aided Drug Design Approach and its Biological Activity
10.3321/j.issn:1000-467X.2001.04.001
- VernacularTitle:计算机辅助设计HER2/neu酪氨酸激酶小分子抑制剂及其生物活性研究
- Author:
Xiao-Feng ZHU
1
;
Yi-Xin ZENG
;
Da-Jun YANG
Author Information
1. Sun Yat-sen University of Medical Sciences
- From:Chinese Journal of Cancer
2001;20(4):341-347
- CountryChina
- Language:Chinese
-
Abstract:
Objective： To discover HER2/neu tyrosine kinase inhibitor through computer-aided drug design approach. Methods： The three-dimensional(3D) structure of HER2/neu and EGFR tyrosine kinase domain was modeled using MODERLAR software. To search database and pick up candidate compounds based 3D structure of HER2/neu tyrosine kinase domain. Inhibition of HER2/neu tyrosine kinase phosphorylation by the compounds was detected using Western blot analysis. Inhibition of cell proliferation was determined by MTT assay. Results： The amino acid identity and similarity between HER2/neu and EGFR kinase domain, insulin receptor kinase domain, FGFR1 kinase domain, Src kinase domain were compared. The identity was 35％ -41％ and the similarity was 52％ -55％ . The 3D structure of HER2/neu and EGFR was obtained by MODERLAR software. Through searching, screening and optimization, the authors found that ST2325 had significantly inhibitory effect on HER2/neu tyrosine kinase phosphorylation with IC50 of 6.6 μ mol/L. The inhibition of HER2/neu phosphorylation was selective and reversible. ST2325 inhibited cell proliferation of HER2/neu-overexpressing MDA-MB-453m1 preferentially compared with EGFR-overexpressing MDA- MB-468, The IC50 values were 29.05 and 60.4 μ mol/L. Conclusion： ST2325 which was discovered through structure-based approach had notable inhibitory effect on HER2/neu tyrosine kinase.
