In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1
In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1
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DOI：
10.1158/1535-7163.mct-06-0543
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发表时间：
2007-02-01
影响因子：
5.7
通讯作者：
Cheung, Mui
中科院分区：
文献类型：
--
作者：
Lansing, Timothy J.;McConnell, Randy T.;Cheung, Mui
Polo-like kinase1(PLK1)在有丝分裂过程中起关键作用，包括有丝分裂进入、纺锤体形成、染色体分离和胞质分裂。PLK1的表达和活性与细胞增殖密切相关。许多研究表明，PLK1在多种肿瘤中表达升高，且高表达往往与预后不良相关。利用多种方法，包括小分子抑制PLK1的功能和/或活性，癌细胞系的凋亡，正常细胞系的细胞周期停滞，以及体内的抗肿瘤活性，已经被观察到。在本研究中，我们研究了一种新型的、选择性的噻吩苯并咪唑三磷酸腺苷-PLK1和PLK3的竞争性抑制剂(5-(5，6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}-thiophene-2-carboxamide，的体外生物活性(称为化合物1)。化合物1对PLK1和PLK3酶具有低的纳米分子活性，并有效地抑制多种肿瘤细胞系的增殖。在肺腺癌细胞系NCI-H460中，化合物1诱导一过性G(2)-M期停滞，有丝分裂梭形缺陷和多核表型导致细胞凋亡，而正常人二倍体成纤维细胞停滞在G2-M期，几乎没有凋亡。我们还描述了一种用于鉴定PLK1的有效细胞内抑制物的细胞学实验。化合物1除了具有治疗癌症的潜力外，还是进一步研究PLK1和PLK3生物学功能的有用工具分子。
Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}-thiophene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G(2)-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G2-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3.