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.
