Naturally occurring homoisoflavonoids function as potent protein tyrosine kinase inhibitors by c-Src-based high-throughput screening
Naturally occurring homoisoflavonoids function as potent protein tyrosine kinase inhibitors by c-Src-based high-throughput screening
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DOI：
10.1021/jm701501x
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发表时间：
2008-08-14
影响因子：
7.3
通讯作者：
Ye, Yang
中科院分区：
文献类型：
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作者：
Lin, Li-Gen;Xie, Hua;Ye, Yang
蛋白酪氨酸激酶(PTK)抑制剂代表了癌症预防的新兴疗法。在我们的研究中，通过使用基于ELISA法的自动高通量筛选策略，在一个正交化合物混合文库(32200个化合物)中，hernatoxylin(26)被鉴定为最显著的c-Src抑制剂之一。有趣的是，苏木精在体外被发现是一种ATP竞争性的广谱PTK抑制剂，其IC50值从纳摩尔到微摩尔水平不等。进一步的研究表明，这种抑制与PTK的磷酸化和随后的下游信号通路有关。苏木素类似物抑制PTK活性的构效关系评估与并行分子对接模拟结果一致：A环上的邻苯二酚部分和类苏木素的三维结构是c-Src靶向活性所必需的。苏木素及其天然类似物被证实是一类新的PTK抑制剂。
Protein tyrosine kinase (PTK) inhibitors represent emerging therapeutics for cancer chernoprevention. In our study, hernatoxylin (26) was identified as one of the most remarkable c-Src inhibitors in an orthogonal compound-mixing library (32200 compounds) by using an ELISA-based automated high-throughput screening (HTS) strategy. Interestingly, hematoxylin was found to be an ATP competitive broad-spectrum PTK inhibitor in vitro, with IC50 values ranging from nanomolar to micromolar level. Further studies showed that such inhibition was associated with the PTK phosphorylation and subsequent downstream signaling pathways. The structure - activity relationship assessment of the PTK inhibitory potency of hematoxylin analogues isolated from Heamatoxylon campechianum was in good agreement with the result of concurrent molecular docking simulation: the catechol moiety in ring A and the hematoxylin-like three-dimensional structure were essential for c-Src-targeted activities. Hematoxylin and its natural analogues were substantially validated to function as a new class of PTK inhibitors.