摘要
背景:Haspin(单倍体生殖细胞特异性核蛋白激酶)是一种非典型的丝氨酸/苏氨酸蛋白激酶,由于Haspin与经典蛋白激酶的低度结构同源性,长期以来被认为是一种无活性的假激酶。然而,在Thr3残基上Haspin催化的组蛋白H3的磷酸化的发现揭示了Haspin在有丝分裂中的重要性,并且提供了有丝分裂磷酸化途径和染色质修饰之间的另一个联系。 结果:在111篇出版物的综述中,我们(1)简要总结了Haspin的催化性质和生理作用,(2)重点介绍了Haspin的结构及其底物识别机制,(3)详细了解了Haspin选择性抑制剂的发展和表征,以及(4)尽管靶向其他蛋白激酶的抑制剂支架概述了Haspin作为常见的脱靶。 结论:Haspin靶向低分子化合物的化学空间尚未得到广泛的探索,但几种支架(如吖啶,β-咔啉或5-碘结核菌素的衍生物)已经成为有希望的抑制剂。在最近的几项研究中,将Haspin纳入用于分析低分子量化合物的蛋白激酶组中,提供了有关Haspin公知的或新型抑制剂的结构亲和力或结构 - 活性关系的有价值的信息。
关键词: 蛋白激酶,Haspin,Dyrk,Clk,Pim,Melk,抑制剂,组蛋白H3
Current Medicinal Chemistry
Title:Structure, Roles and Inhibitors of a Mitotic Protein Kinase Haspin
Volume: 24 Issue: 21
关键词: 蛋白激酶,Haspin,Dyrk,Clk,Pim,Melk,抑制剂,组蛋白H3
摘要: Background: Haspin (haploid germ cell-specific nuclear protein kinase) is an atypical serine/threonine-protein kinase that was for a long time considered an inactive pseudokinase due to low degree of structural homology of Haspin with the ‘classical’ protein kinases. However, the discovery of Haspin-catalyzed phosphorylation of histone H3 at Thr3 residue unveiled importance of Haspin in mitosis and provided yet another link between mitotic phosphorylation pathways and chromatin modifications.
Results: In this review of 111 publications, we have (1) briefly summarized catalytic properties and physiological roles of Haspin, (2) focussed on the architecture of Haspin and mechanisms behind its substrate recognition, (3) provided detailed insight into the advances in the development and characterization of Haspin-selective inhibitors, and (4) given overview of inhibitor scaffolds that despite targeting other protein kinases feature Haspin as a common off-target. Conclusion: The chemical space of Haspin-targeting low-molecular-weight-compounds has not yet been widely explored, but several scaffolds (e.g., derivatives of acridine, β-carboline or 5-iodotubercidin) have emerged as promising inhibitors. The inclusion of Haspin into protein kinase panels for profiling of low-molecular-weight-compounds in several recent studies has provided valuable information about the structure-affinity or structure-activity relationship of well-known or novel inhibitors towards Haspin.Export Options
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Cite this article as:
Structure, Roles and Inhibitors of a Mitotic Protein Kinase Haspin, Current Medicinal Chemistry 2017; 24 (21) . https://dx.doi.org/10.2174/0929867324666170414155520
DOI https://dx.doi.org/10.2174/0929867324666170414155520 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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