University of South Carolina, South Carolina College of Pharmacy, Drug Discovery and Biomedical Sciences , Columbia, SC, 29208 , USA +1 803 576 5684 ;
Expert Opin Drug Discov. 2014 Jul;9(7):773-89. doi: 10.1517/17460441.2014.918100. Epub 2014 May 12.
Polo-like kinase (PLK)1 is the most studied of the PLK family and is a serine/threonine kinase that plays pivotal roles in many aspects of mitosis and hence its deregulation is prevalent in various malignant tumor types.
In this review, the authors discuss the relevancy of PLK1 and other PLK members as oncology targets in light of known roles of these kinases and the observed phenotypic consequence of downregulating their activity, depending on how they are targeted. Furthermore, they also discuss the pathways mutated in cancer that have been shown to enhance sensitivity toward PLK1 inhibitors in the context of tumor types that possess these molecular defects. They also summarize preclinical and clinical investigations that have been undertaken for both ATP and non-ATP competitive inhibitors.
PLKs 2, 3 and 5 are primarily linked with tumor suppressor functions and as PLK1 is the most validated anticancer drug target, selective inhibitors for its activities are most likely to result in effective therapeutics with reduced side effects. In this regard, the polo box domain can be targeted to generate selective inhibitors of PLK1 while preventing inhibition of kinases outside of this family. Recent studies confirming the synthetic lethality of other molecular defects with PLK1 can be exploited to obtain tumor selective apoptosis in p53, KRAS and PTEN mutant cancers.
丝氨酸/苏氨酸激酶 Polo 样激酶 1（PLK1）是 PLK 家族中研究最深入的激酶，在有丝分裂的许多方面发挥着关键作用，因此其失调在各种恶性肿瘤类型中普遍存在。
在这篇综述中，作者根据这些激酶的已知作用以及下调其活性的观察到的表型后果，讨论了 PLK1 和其他 PLK 成员作为肿瘤学靶点的相关性，具体取决于它们的靶向方式。此外，他们还讨论了在具有这些分子缺陷的肿瘤类型中，已显示出增强对 PLK1 抑制剂敏感性的癌症中突变的途径。他们还总结了针对 ATP 和非 ATP 竞争性抑制剂的临床前和临床研究。
PLK2、PLK3 和 PLK5 主要与肿瘤抑制功能相关，而 PLK1 是最有效的抗癌药物靶点，因此针对其活性的选择性抑制剂很可能会产生副作用较小的有效治疗方法。在这方面，可以靶向 Polo 盒结构域来生成针对 PLK1 的选择性抑制剂，同时防止抑制该家族以外的激酶。最近的研究证实了其他分子缺陷与 PLK1 的合成致死性，可以利用这一点在 p53、KRAS 和 PTEN 突变型癌症中获得肿瘤选择性凋亡。
