Current Medicinal Chemistry             Katrin Kestav, Asko Uri and Darja Lavogina * University of Tartu, Institute of Chemistry, Ravila 14A, Tartu 50411, Estonia A R T I C L E H I S T O R Y Received: January 26, 2017 Revised: March 26, 2017 Accepted: April 10, 2017 DOI: 10.2174/0929867324666170414155520 Abstract: 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 pseu- dokinase 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 mi- totic phosphorylation pathways and chromatin modifications. Results: In this review of 111 publications, we have (1) briefly summarized catalytic proper- ties and physiological roles of Haspin, (2) focussed on the architecture of Haspin and mecha- nisms 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 pro- tein kinase panels for profiling of low-molecular-weight-compounds in several recent studies has provided valuable information about the structure-affinity or structure-activity relation- ship of well-known or novel inhibitors towards Haspin. Keywords: Protein kinase, Haspin, Dyrk, Clk, Pim, Melk, inhibitor, histone H3. 1. INTRODUCTION Haspin (haploid germ cell-specific nuclear protein kinase), also known as Gsg2 (germ cell-specific gene 2 protein), is an atypical protein kinase (PK) which shares low sequence homology with the ‘classical’ PKs of human kinome [1-4]. In humans, the gene encoding Haspin protein (GSG2) is located at chromosome 17p13.2/13.3, a region that shows loss of heterozygos- ity in several tumors [5, 6]. Haspin gene is abundant throughout the phyloge- netic tree, featuring homologues in a variety of organ- isms, including yeasts, plants, flies, fish, and mammals [2, 7]. Most of the organisms possess 1-2 homologues of Haspin, with the exception of nematode C. elegans that has 3 homologues and 16 Haspin-related genes *Address correspondence to this author at the University of Tartu, Institute of Chemistry, Ravila 14A, Tartu 50411, Estonia; Tel: +372 737 5250; E-mail: darja.lavogina@ut.ee [2, 8]. The catalytic domain of Haspin is located at the C-terminus of the protein and is evolutionarily well conserved, whereas the sequence of N-terminal part of the protein varies greatly between the organisms [1, 4, 8, 9]. Haspin mRNA is mostly present in testis, but de- spite the origins of its name, Haspin is not a germ cell- specific PK [3, 8, 10]. At lower concentration, Haspin protein is expressed also in somatic cells throughout the cell cycle [11-13]. In interphase cells, Haspin shows nuclear localization; in early mitosis, Haspin becomes associated with condensed chromosomes and although present along chromosomal arms, is concen- trated in central region [11, 14, 15]. Studies on fission yeast and on mice indicated that Haspin is recruited to centromeric chromatin by the sister chromatid cohesion protein Pds5 [14, 16]; this mechanism has been pro- posed to ensure centromeric localization of Haspin also in other organisms. Such localization persists until ana- 1875-533X/17 $58.00+.00 © 2017 Bentham Science Publishers Send Orders for Reprints to reprints@benthamscience.ae 2276 Current Medicinal Chemistry, 2017, 24, 2276-2293 REVIEW ARTICLE Structure, Roles and Inhibitors of a Mitotic Protein Kinase Haspin