A series of beta-carboline derivatives inhibit the kinase activity of PLKs.
A series of beta-carboline derivatives inhibit the kinase activity of PLKs.
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一系列β-咔啉衍生物抑制 PLK 的激酶活性
DOI：
10.1371/journal.pone.0046546
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Si S
中科院分区：
文献类型：
--
作者：
Han X;Zhang J;Guo L;Cao R;Li Y;Li N;Ma Q;Wu J;Wang Y;Si S
Polo样激酶在有丝分裂事件的有序执行中发挥重要作用，已鉴定出4种哺乳动物PLK家族成员。越来越多的证据表明PLK 1是一个有吸引力的抗癌药物靶点。本论文合成了一系列β-咔啉衍生物，并对其中的三个化合物DH 281、DH 285和DH 287进行了结构鉴定。我们采用了各种生化和细胞的方法来确定这些化合物对PLK 1和其他有丝分裂激酶的活性和细胞周期进程的影响。我们发现这三种化合物在体外都能选择性地抑制纯化的PLK 1、PLK 2和PLK 3的激酶活性。它们对许多癌细胞系显示出较强的抗肿瘤活性，具有相对较低的微摩尔IC 50，但对非癌细胞的毒性相对较低（MRC 5）。这些化合物可诱导HeLa细胞在G2/M期和S期明显聚集，并可引发细胞凋亡。尽管MRC 5细胞在用这些化合物处理后显示出明显的S期阻滞，但G2/M阻滞和细胞凋亡不太显著，表明正常细胞和癌细胞之间的不同敏感性。我们还发现，用这些药物处理的HeLa细胞表现出单极纺锤体和增加的Wee 1蛋白水平，这是用PLK 1抑制剂处理的细胞的特征。总之，这些结果表明，DH 281、DH 285和DH 287 β-咔啉化合物是具有癌症治疗潜力的新PLK抑制剂。
Polo-like kinases play an essential role in the ordered execution of mitotic events and 4 mammalian PLK family members have been identified. Accumulating evidence indicates that PLK1 is an attractive target for anticancer drugs. In this paper, a series of beta-carboline derivatives were synthesized and three compounds, DH281, DH285 and DH287, were identified as potent new PLK inhibitors. We employed various biochemical and cellular approaches to determine the effects of these compounds on the activity of PLK1 and other mitotic kinases and on cell cycle progression. We found that these three compounds could selectively inhibit the kinase activity of purified PLK1, PLK2 and PLK3 in vitro. They show strong antitumor activity against a number of cancer cell lines with relatively low micromolar IC50s, but are relatively less toxic to non-cancer cells (MRC5). Moreover, these compounds could induce obvious accumulation of HeLa cells in G2/M and S phases and trigger apoptosis. Although MRC5 cells show clear S-phase arrest after treatment with these compounds, the G2/M arrest and apoptosis are less insignificant, indicating the distinct sensitivity between normal and cancer cells. We also found that HeLa cells treated with these drugs exhibit monopolar spindles and increased Wee1 protein levels, the characteristics of cells treated with PLK1 inhibitors. Together, these results demonstrate that DH281, DH285 and DH287 beta-carboline compounds are new PLK inhibitors with potential for cancer treatment.
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