Evaluation of active recombinant catalytic domain of human ErbB-2 tyrosine kinase, and suppression of activity by a naturally derived inhibitor, ZH-4B

• Published in: Biochimica et biophysica acta Vol. 1673; no. 3; pp. 186 - 193
• Main Authors: Guo, Xiao-Ning, Zhong, Li, Zhang, Xiu-Hua, Zhao, Wei-Min, Zhang, Xiong-Wen, Lin, Li-Ping, Ding, Jian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 04.08.2004
• Subjects: Animals; Anti-cancer drug; Catalytic Domain; Cations, Divalent - metabolism; Cell Line, Tumor; Drugs, Chinese Herbal - pharmacology; Enzyme Inhibitors - pharmacology; ErbB-2; Humans; Phosphorylation; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - chemistry; Receptor, ErbB-2 - metabolism; Recombinant Proteins - metabolism; Substrate Specificity; Tyrosine kinase inhibitor; ZH-4B; ErbB-2; PBS; SDS; Tyrosine kinase inhibitor; EGF; DMSO; DTT; PMSF; ZH-4B; Anti-cancer drug; RTKs; ATP
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2004.04.015

Human cancers frequently express high levels of ErbB-2 tyrosine kinase, which is associated with aggressive tumor behavior and poor prognosis. ErbB-2 is thus a promising target for cancer therapy. Here we express the catalytic domain of ErbB-2 as a soluble active kinase, and investigate the correlations between its activity and kinase concentration, ATP concentration, substrate concentration and divalent cation type. A simple and effective screening model is established to identify and evaluate potential inhibitors of ErbB-2 kinase. ZH-4B, a naturally derived small molecule compound that potently inhibits ErbB-2 kinase activity with an IC50 value of 2.45±0.56 μM, is identified. In SK-OV-3 human ovarian cancer cells and SK-BR-3 human breast carcinoma cells, ZH-4B blocks epidermal growth factor (EGF)-induced phosphorylation of ErbB-2 in a dose-dependent manner. Our data collectively indicate that ZH-4B is a potential novel anti-cancer agent that deserves further investigation.