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Abstract：
Polo-like kinase (PLK1) has been identified as a potential target for cancer treatment. Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain (PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethyl-benzofuran-2-carboxylic acid ethyl ester (designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis. This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest-a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.
摘要：
Polo样激酶（PLK1）已被确定为癌症治疗的潜在靶标。尽管已经研究了许多小分子作为PLK1抑制剂，其中许多显示出有限的选择性。PLK1拥有一个监管域，Polobox域(PBD)，具有激酶活性和底物识别的关键调节功能。我们报道了3-溴甲基-苯并呋喃-2-甲酸乙酯（命名为：MCC1019）作为靶向PLK1PBD的选择性PLK1抑制剂。将细胞毒性和基于荧光偏振的筛选应用于1162种药物样化合物的文库，以鉴定PLK1PBD的潜在抑制剂。化合物MC1019对PLK1PBD的活性用荧光偏振和微尺度热泳法证实。该化合物对PLK1比PLK2和PLK3具有特异性。MCC1019在一组不同的癌细胞系中显示出细胞毒性活性。在A549肺腺癌细胞中的机制研究表明，MCC1019通过失活AKT信号通路诱导细胞生长抑制，它还诱导了长时间的有丝分裂停滞——一种被称为有丝分裂灾难的现象，随后通过细胞凋亡和坏死立即死亡。MCC1019在小鼠肺癌模型中体内显著抑制肿瘤生长，而不影响体重或重要器官大小，并减少了肺部转移灶的生长。我们提出MCC1019作为有希望的抗癌候选药物。
