Structure, Roles and Inhibitors of a Mitotic Protein Kinase Haspin

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.

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.

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.