丝裂素活化蛋白激酶（MAPK）与激酶1和2（MNK1和MNK2）相互作用作为癌症治疗的靶标：MNK抑制剂开发的最新进展。,Current Medicinal Chemistry

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丝裂素活化蛋白激酶（MAPK）与激酶1和2（MNK1和MNK2）相互作用作为癌症治疗的靶标：MNK抑制剂开发的最新进展。
Current Medicinal Chemistry ( IF 3.5 ) Pub Date : 2017 Feb 03 , DOI: 10.2174/0929867324666170203123427
Agnieszka Dreas ₁ , Maciej Mikulski ₁ , Mariusz Milik ₁ , Charles-Henry Fabritius ₁ , Krzysztof Brzózka ₁ , Tomasz Rzymski ₁

Affiliation

背景：MNK1和MNK2是与MAP激酶相互作用的丝氨酸/苏氨酸激酶，被RAS和MAPK信号通路激活，并参与蛋白质翻译的调控。两种激酶都会在保守的丝氨酸209上磷酸化翻译起始因子eIF4E。过度活化的eIF4E可以作为癌基因，在体外和体内均有助于转化，并在多种类型的癌症中高度表达。有趣的是，同时缺少Mnk1和Mnk2的基因敲除小鼠没有任何明显的表型。最近，首批双重MNK1 / 2抑制剂已与多西他赛联合治疗NSCLC和其他实体瘤，进入临床试验。结果，人们对新型选择性MNK1 / 2抑制剂的开发和表征越来越感兴趣。方法：为了收集科学资源，已经对可用的书目数据库进行了文献检索，重点是MNKs激酶的最新和选择性抑制剂。本文中使用的其他有价值的信息资源包括可用的专利和会议报告，它们为着重于抑制MNK的正在进行的开发计划提供了概述。在许多情况下，收集到的结果使得能够进行结构-活性关系的分析，并进一步了解选择性和细胞作用方式。使用从PDB数据库（www.rcsb.org）下载的MNK的X射线结构进行结构比较，并使用开源软件包Pymol（pymol.org）进行可视化。使用Moebitz等人生成的结构比对来选择MNKs结构的关键结构特征。2015年和内部开发的Python脚本。结果：提出的评论是对几乎所有对MNK1 / 2激酶具有明显抑制活性的主要化学类别的全面概述。近年来，主要由制药公司提交的140篇论文以及专利申请已包括在本评价中。五十一篇论文介绍了MNK在实体瘤和血液系统恶性肿瘤的发展和进程中的作用，特别是在帽依赖性翻译的背景下，其受eIF4E磷酸化调节。引入首批临床化合物是验证MNK作为肿瘤学可行靶标的重要步骤。令人惊讶的是，关于使用选择性MNK1 / 2抑制剂治疗细胞的相关作用知之甚少。事实证明，大多数用作化学探针的化合物都是弱和/或非选择性抑制剂。37篇论文（最近六年中的27篇）记录了新型MNK抑制剂的开发已取得的巨大进展。几种不同的新型化学支架在低纳摩尔范围内显示出高亲和力，并显示出有希望的选择性迹象。这些化合物通常在重组激酶的生化活性与通过eIF4E Ser209的水平测量的细胞靶标接合之间显示出良好的相关性。出乎意料的是，关于发挥的细胞功效，各种MNK探针之间存在显着差异。为了表征细胞并关键地依赖于MNK的激酶活性，需要做进一步的工作。额外的药效学研究应将观察到的对eIF4E生物标志物水平的影响与预期功效更好地联系起来，这可能需要持续和接近完全抑制才能获得所需的抗癌活性。根据现有数据，我们将描述的抑制剂分类为I型，II型，III型（变构）和VI型（共价）。另外，已经描述了通过降解而不是抑制作用的非共价大环化合物和视黄酰胺的实例。结论：关于新型，选择性MNK1 / 2激酶抑制剂的发展的报道越来越多，这促使我们以本综述的形式总结了最重要的成就和当前的挑战。提出的结果可能有助于为针对MNK药理学抑制作用的实验选择最佳探针。一流的MNK1 / 2抑制剂正在进行的临床试验结果将为化学发展确定进一步的方向。一方面，基因敲低研究表明选择性方法具有明显的安全益处。另一方面，对可用抑制剂的严格修订表明，新的药物化学策略对于增加亲和力和合理参与其他靶标是必要的，目的是提高治疗效果。

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Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) as targets for cancer therapy: recent progress in the development of MNK inhibitors.

BACKGROUND: MNK1 and MNK2 are MAP kinase-interacting serine/threonine kinases, which are activated by RAS and MAPK signaling pathways and are involved in regulation of protein translation. Both kinases phosphorylate translation initiation factor eIF4E on a conserved serine 209. Overactivated eIF4E can act as an oncogene and contribute to the transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, knockout mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype. Recently first dual MNK1/2 inhibitors have entered clinical trials as a combinational therapy with docetaxel in NSCLC and in other solid tumors. As a result there is a growing interest in development and characterization of novel selective MNK1/2 inhibitors. METHODS: A literature search of available bibliographic databases has been done in order to collect scientific resources, with an emphasis on the most recent and selective inhibitors of MNKs kinases. Additional valuable sources of information used in the article include available patents and conference reports, which provide an overview for ongoing development programs focused on the inhibition of MNKs. Collected results in many cases enabled analysis of structure-activity relationship and additional insight into selectivity, and cellular mode of action. Structure comparisons were performed using X-ray structures of MNKs downloaded from PDB database (www.rcsb.org) and visualized using an open source package Pymol (pymol.org). The key structural features for MNKs structures were selected using structural alignments generated by Moebitz et al. 2015, and internally developed Python scripts. RESULTS: Presented review is a comprehensive overview of virtually all major chemical classes with a significant inhibitory activity on MNK1/2 kinases. One hundred and forty papers together with patent applications, filed in recent years, mostly by pharmaceutical companies, were included in this review. Fifty-one papers presented roles of MNKs in the development and progression of solid tumors and hematological malignancies, particularly in the context of cap-dependent translation, regulated by phosphorylation of eIF4E. Introduction of first clinical compounds is an important step in the process of validation MNKs as viable targets in oncology. Surprisingly very little is known about effects associated with treatment of cells using selective MNK1/2 inhibitors. Majority of compounds used as chemical probes proved to be either weak and/or non-selective inhibitors. Thirty-seven papers (of which twenty-seven of the last six years) document an enormous progress that has been made in the development of novel MNK inhibitors. Several different and novel chemical scaffolds have shown high affinity in low nanomolar range and promising signs of selectivity. These compounds in general display good correlation between biochemical activity on recombinant kinases and cellular target engagement measured by levels of eIF4E Ser209. Unexpectedly, there is a significant discrepancy between various MNK probes regarding exerted cellular efficacy. Further work is needed in order to characterize cells and process crucially dependent on the kinase activity of MNKs. Additional pharmacodynamics studies should better link observed effects on the level of eIF4E biomarker with expected efficacy, which may require sustain and near complete inhibition to attain desirable anti- cancer activity. Based on available data we have classified described inhibitors as Type I, Type II, Type III (allosteric) and Type VI (covalent). Additionally, examples of non-covalent macrocyclic compounds and retinamides, which act via degradation instead of inhibition have been described. CONCLUSION: There is a growing number of reports on developments of novel, selective inhibitors of MNK1/2 kinases, what prompted us to summarize the most important achievements and current challenges in a form of this review. Presented results may help to select optimal probes for experiments aimed at the consequences of pharmacological inhibition of MNKs. Results of ongoing clinical trials of first-in-class MNK1/2 inhibitors will define further directions of chemical development. On the one hand, genetic knockdown studies indicated clear safety benefits of selective approach. On the other, critical revision of available inhibitors indicates that novel medicinal chemistry strategies would be necessary for increased affinity and rational engagement of additional targets, aimed at improved therapeutic efficacy.

更新日期：2017-01-31

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