The Mitotic Protein Kinase Haspin and Its Inhibitors

Abstract

Haspin is an atypical serine/threonine protein kinase essential to mitosis. Unlike other protein kinases, its kinase domain does not require phosphorylation in order to be activated and bears very high substrate specificity and selectivity. Few substrates have been identified so far. Haspin phosphorylation on threonine 3 of Histone H3 from prophase to anaphase participates to centromeric Aurora B localization and ensures proper kinetochore-microtubule attachment. Haspin is also involved in the maintenance of centromeric cohesion and the mitotic spindle. Inhibitors have been developed and provided tools to dissect Haspin function. The kinase is now considered as a potential therapeutic target against cancer. We discuss here the latest findings on this essential mitotic protein.

A Peak of H3T3 Phosphorylation Occurs in Synchrony with Mitosis in Sea Urchin Early Embryos

“…The use of genetic tools and the discovery of specific inhibitors targeting Haspin have contributed decisively to the functional characterisation of this kinase, offering in parallel an opportunity to study the biological significance of H3T3 phosphorylation [28]. Haspin depletion by RNA interference in mitotically active cells results in low levels of T3H3ph and promotes the accumulation of cells assuming a late prometaphase aspect [18].…”

Synthesis and Kinase Inhibitory Potencies of Pyrazolo[3,4-g]isoquinolines

“…Haspin is an atypical serine/threonine kinase involved in the phosphorylation of Thr3 (threonine 3) of Histone H3 in mitotic cells. Due to its essential role in mitosis, Haspin appeared as an interesting target for cancer therapy [ 3 ]. However, as frequently reported (e.g., [ 4 , 5 ]), Haspin inhibitors cross-inhibited other protein kinases such as CLK1 (cdc2-like kinase 1), DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) or CDK9 (cyclin-dependent kinase 9).…”