Department of Obstetrics and Gynecology, Medical School, Goethe-University, Frankfurt, Germany.
Cell Cycle. 2010 Feb 15;9(4):761-73. doi: 10.4161/cc.9.4.10644. Epub 2010 Feb 16.
Human polo-like kinase 1 (Plk1), a key regulator of mitosis, is overexpressed in various human tumors. It is a negative prognostic factor for cancer patients and a measure for the aggressiveness of a tumor. Thus, targeting Plk1 might be a promising approach for cancer therapy. Kinase inhibitors are divided in type I inhibitors, targeting the highly conserved active conformation, and the more selective type II inhibitors, targeting the inactive conformation of kinases. We analyzed our previously identified type II Plk1 inhibitor SBE13 which is able to inhibit Plk1 activity. To determine its ability to induce cell death in cancer cells, we applied kinase assays, western blot analyses, FACScan analyses, Caspase assays and immunofluorescence studies. We detected decreased cell proliferation, delayed progression through the cell cycle in lower SBE13 concentrations, a G(2)/M arrest using higher SBE13 concentrations followed by apoptosis, and abnormal mitotic figures. Notably, SBE13 did not influence activity of other kinases (Plk2, Plk3, Aurora A), indicating the selectivity of this type II Plk1 inhibitor. This study suggests that Plk1 kinase inhibitors targeting the inactive conformation of Plk1 may be considered for the development of cancer therapeutics.
人源 Polo 样激酶 1（Plk1）是有丝分裂的关键调节因子，在各种人类肿瘤中过度表达。它是癌症患者的预后不良因素，也是肿瘤侵袭性的衡量指标。因此，靶向 Plk1 可能是癌症治疗的一种有前途的方法。激酶抑制剂分为针对高度保守的活性构象的 I 型抑制剂和针对激酶非活性构象的更具选择性的 II 型抑制剂。我们分析了我们之前鉴定的能够抑制 Plk1 活性的 II 型 Plk1 抑制剂 SBE13。为了确定其在癌细胞中诱导细胞死亡的能力，我们应用了激酶测定、western blot 分析、FACScan 分析、Caspase 测定和免疫荧光研究。我们检测到细胞增殖减少，较低浓度的 SBE13 使细胞周期进展延迟，较高浓度的 SBE13 导致 G2/M 期阻滞，随后发生细胞凋亡和有丝分裂异常。值得注意的是，SBE13 不影响其他激酶（Plk2、Plk3、Aurora A）的活性，表明这种 II 型 Plk1 抑制剂具有选择性。这项研究表明，针对 Plk1 非活性构象的 Plk1 激酶抑制剂可能被考虑用于癌症治疗的开发。
