Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-molecule inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concentrations. The compound potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated intravenous dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochemistry and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers.

中文翻译：

---

BI 2536 是一种有效的选择性 Polo 样激酶 1 抑制剂，可抑制体内肿瘤生长。


细胞分裂周期的精细绘制，特别是有丝分裂激酶信号通路的识别，为癌症药物的发现提供了新的机会。作为真核物种有丝分裂进展过程中多个步骤的关键调节因子，丝氨酸/苏氨酸特异性 Polo 样激酶 1 (Plk1) 在恶性细胞中高度表达，并可作为特定人类癌症类型的阴性预后标志物。在这里，我们报告发现了一种有效的哺乳动物 Plk1 小分子抑制剂 BI 2536，它可以在低纳摩尔浓度下抑制 Plk1 酶活性。该化合物可有效引起有丝分裂停滞并诱导不同组织来源和癌基因组特征的人类癌细胞系凋亡。 BI 2536 可抑制裸鼠体内人类肿瘤异种移植物的生长，并通过耐受性良好的静脉给药方案诱导大肿瘤消退。在治疗的肿瘤中，细胞停滞在中期，积累磷酸组蛋白 H3，并含有异常的有丝分裂纺锤体。这种有丝分裂停滞之后是细胞凋亡激增，可以通过免疫组织化学和无创光学和磁共振成像检测到。为了解决 Plk1 抑制的治疗潜力，BI 2536 已进入局部晚期或转移性癌症患者的临床研究。