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：

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BI 2536是polo样激酶1的有效和选择性抑制剂，可在体内抑制肿瘤生长。

细胞分裂周期的精细映射，尤其是有丝分裂激酶信号传导途径的鉴定，为癌症药物发现提供了新的机会。丝氨酸/苏氨酸特异性Polo样激酶1（Plk1）作为真核生物有丝分裂过程中多个步骤的关键调节因子，在恶性细胞中高度表达，在特定人类癌症类型中作为阴性预后标志物。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，该抑制剂在低纳摩尔浓度下抑制Plk1酶活性。该化合物有效地导致有丝分裂停滞并诱导具有不同组织起源和癌基因组特征的人癌细胞系中的细胞凋亡。BI 2536在耐受良好的静脉给药方案下可抑制裸鼠中人肿瘤异种移植的生长，并诱导大肿瘤消退。在已治疗的肿瘤中，细胞停滞在前中期，积累了磷酸组蛋白H3，并含有异常的有丝分裂纺锤体。这种有丝分裂阻滞之后是凋亡的激增，可通过免疫组织化学以及非侵入性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已针对患有局部晚期或转移性癌症的患者进行了临床研究。可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已进入针对局部晚期或转移性癌症患者的临床研究。可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已进入针对局部晚期或转移性癌症患者的临床研究。