Several inhibitors of the Plk1 Polo-Box Domain turn out to be non-specific protein alkylators
Several inhibitors of the Plk1 Polo-Box Domain turn out to be non-specific protein alkylators
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DOI：
10.1080/15384101.2017.1325043
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Normandin, Karine
中科院分区：
文献类型：
--
作者：
Archambault, Vincent;Normandin, Karine
近十年来，人们对 Polo 样激酶 1 (Plk1) 蛋白相互作用的化学抑制剂的开发产生了浓厚的兴趣。 Plk1 是细胞分裂周期的主要调节因子，控制着多种底物。它是癌症药物开发的一个有前途的目标。 Plk1 激酶结构域的抑制剂在临床试验中取得了一些成功。然而，它们并不是完全有选择性的。原则上，Plk1 也可以通过干扰其蛋白质相互作用结构域 Polo-Box 结构域 (PBD) 来抑制。 PBD 的选择性化学抑制剂将成为探测 Plk1 的 PBD 依赖性功能的工具，并且可能有利于癌症治疗。 Poloxin 和百里醌作为 PBD 抑制剂的发现表明可以鉴定出小的、细胞渗透性的化学抑制剂。随后的其他努力，包括我们的努力，报告了能够阻断 PBD 的其他分子。现在很清楚，不幸的是，大多数这些化合物都是非特异性蛋白质烷基化剂（此处定义为通过碳共价添加的基团），它们几乎没有或没有开发真正的 Plk1 PBD 特异性药物的潜力。对使用这些化合物研究 Plk1 感兴趣的生物学家应该注意这种情况。需要进一步努力开发选择性的、细胞渗透性的 PBD 抑制剂。
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD). Selective chemical inhibitors of the PBD would constitute tools to probe for PBD-dependent functions of Plk1 and could be advantageous in cancer therapy. The discovery of Poloxin and thymoquinone as PBD inhibitors indicated that small, cell-permeable chemical inhibitors could be identified. Other efforts followed, including ours, reporting additional molecules capable of blocking the PBD. It is now clear that, unfortunately, most of these compounds are non-specific protein alkylators (defined here as groups covalently added via a carbon) that have little or no potential for the development of real Plk1 PBD-specific drugs. This situation should be minded by biologists potentially interested in using these compounds to study Plk1. Further efforts are needed to develop selective, cell-permeable PBD inhibitors.