Evaluation of active recombinant catalytic domain of human ErbB-2 tyrosine kinase, and suppression of activity by a naturally derived inhibitor, ZH-4B
Evaluation of active recombinant catalytic domain of human ErbB-2 tyrosine kinase, and suppression of activity by a naturally derived inhibitor, ZH-4B
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DOI：
10.1016/j.bbagen.2004.04.015
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发表时间：
2004-08-04
影响因子：
3
通讯作者：
Ding, J
中科院分区：
文献类型：
--
作者：
Guo, XN;Zhong, L;Ding, J
人类癌症经常表达高水平的ErbB-2酪氨酸激酶，这与肿瘤的侵袭性和预后不良有关。因此，ErbB-2是一个很有希望的癌症治疗靶点。在这里，我们将ErbB-2的催化结构域表达为一个可溶的活性激酶，并研究了它的活性与激酶浓度、ATP浓度、底物浓度和二价阳离子类型的关系。建立了一种简单有效的筛选模型来鉴定和评价ErbB-2激酶的潜在抑制剂。ZH-4B是一种天然衍生的小分子化合物，能有效地抑制ErbB-2激酶的活性，其IC50值为2.45±0.56um。在SK-OV-3人卵巢癌细胞和SK-BR-3人乳腺癌细胞中，ZH-4B以剂量依赖的方式阻断表皮生长因子(EGF)诱导的ErbB-2的磷酸化。我们的数据综合表明，ZH-4B是一种潜在的新型抗癌药物，值得进一步研究。(C)2004爱思唯尔B.V.保留所有权利。
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 muM, 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. (C) 2004 Elsevier B.V. All rights reserved.