Polo-like kinase 1 as target for cancer therapy.
Polo-like kinase 1 as target for cancer therapy.
复制标题
DOI：
10.1186/2162-3619-1-38
复制
发表时间：
2012-12-10
影响因子：
10.9
通讯作者：
Efferth T
中科院分区：
文献类型：
--
作者：
Weiß L;Efferth T
Polo-like kinase1(Plk1)是一种有趣的分子，既是一种生物标志物，也是高度特异的癌症治疗的靶点，原因有几个。首先，它在许多癌症中过度表达，可以作为监测Plk1抑制剂治疗效果的生物标志物。此外，Plk1酶只在分裂细胞中表达，是细胞周期的主要调节因子。它控制进入有丝分裂，并调节纺锤体检查点。Plk1在正常细胞中的表达远不如在癌细胞中的表达强，这使得Plk1成为癌症特异性小分子药物开发的识别靶点。体外和体内的RNA干扰实验表明，下调Plk1的表达代表了癌症治疗的一个有吸引力的概念。多年来，已经发现了许多Plk1抑制剂。其中许多抑制剂是与三磷酸腺苷竞争底物结合部位的物质。ATP竞争性抑制剂BI 6727目前正在癌症患者身上进行临床测试。另一种正在开发中的药物Poloxin是Plk1的第一个Polo-box结构域抑制剂。该化合物是从黑种草中提取的天然产物百里香酚的衍生物。一种新的很有前途的策略是合成双功能抑制剂，将ATP抑制剂的高结合亲和力和竞争性抑制剂的特异性结合起来。
Polo-like kinase 1 (Plk1) is an interesting molecule both as a biomarker and as a target for highly specific cancer therapy for several reasons. Firstly, it is over-expressed in many cancers and can serve as a biomarker to monitor treatment efficacy of Plk1 inhibitors. Furthermore, the Plk1 enzyme is expressed only in dividing cells and is a major regulator of the cell cycle. It controls entry into mitosis and regulates the spindle checkpoint. The expression of Plk1 in normal cells is not nearly as strong as that in cancer cells, which makes Plk1 a discriminating tartget for the development of cancer-specific small molecule drugs. RNA interference experiments in vitro and in vivo have indicated that downregulation of Plk1 expression represents an attractive concept for cancer therapy. Over the years, a number of Plk1 inhibitors have been discovered. Many of these inhibitors are substances that compete with ATP for the substrate binding site. The ATP-competitive inhibitor BI 6727 is currently being clinically tested in cancer patients. Another drug in development, poloxin, is the first Polo-box domain inhibitor of Plk1. This compound is a derivative of the natural product, thymoquinone, derived from Nigella sativa. A novel and promising strategy is to synthesize bifunctional inhibitors that combine the high binding affinity of ATP inhibitors with the specificity of competitive inhibitors.