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  • Introduction Epigenetic mechanisms modulate heritable phenot


    Introduction Epigenetic mechanisms modulate heritable phenotypic changes that are not dictated by changes in DNA sequences. The link between epigenetic modifications and cancer development has been established [1], [2]. Histone modifications represent an important class of epigenetic mechanisms that could be targeted by drugs. The post-translational modifications of histones including methylation, acetylation, ubiquitination, phosphorylation and sumoylation regulate chromatin structure and affect the transcription of various genes [3]. As such intense efforts have been dedicated to the discovery and development of small molecule inhibitors of enzymes that control histone modifications as well as other epigenetic modification enzymes in various cancers [4], [5], [6], [7], [8], [9]. Histone phosphorylation and de-phosphorylation are tightly regulated by epigenetic kinases and phosphatases [3], [10]. The phosphorylation of N-terminal tail of histone H3 at residues such as Thr3, S10, Thr11 and S28 has been well documented to regulate mitosis and meiosis in various life forms [3], [10]. Haspin (haploid germ cell-specific protein kinase), a serine/threonine kinase is involved in histone phosphorylation, particularly at Thr3 (H3T3) during mitosis [11], [12]. Haspin is expressed in several cell types and the upregulation or activation of haspin leads to H3T3 phosphorylation [3]. Dai et al. demonstrated the vital role of haspin in chromosome alignment by showing that depletion of haspin via RNA interference resulted in decreased H3T3 phosphorylation, leading to the misalignment of chromosomes during metaphase [12]. Hence haspin is thought to play a role in chromosome segregation and might be important in tumor formation [11]. Despite the great potential of haspin being a target for anticancer therapy, only a handful of inhibitors have been documented [13], [14], [15], [16]. CHR-6494, a haspin kinase inhibitor, was demonstrated to also possess antitumor properties against melanoma, colon, breast and cervical cancers [13], [17]. CHR-6494 caused a G2/M d-glucose sale arrest consistent with the role of haspin in mitosis [11], [12], [13], [17]. Here we report that compounds containing the 3H-pyrazolo [4,3-f]quinoline scaffold potently inhibit haspin kinase. The compounds also possess anticancer activities against colon, cervical and skin cancers.
    Conclusions In this report we have identified inhibitors of haspin kinase activity and demonstrated their ability to inhibit cancer cell proliferation. HSD972 and HSD929 were the most potent inhibitors with nanomolar IC50 values for the inhibition of haspin activity. Both compounds also inhibited HCT116 and HeLa proliferation at single digit micromolar concentrations. The ease of synthesis of the reported compounds (a one-flask synthesis) makes these novel pyrazolo[4,3-f]quinoline-containing kinase inhibitors ideal lead compounds to develop into anticancer therapeutics.
    Introduction The protein kinases constitute a large group of enzymes in eukaryotes. These enzymes catalyse the transfer of the γ-phosphate of ATP (or GTP) to generate phosphate monoesters using the hydroxyl groups of many proteins. Depending on the proteins involved, this reaction results in either serine/threonine kinases or tyrosine kinases. These protein kinases are related by virtue of their homologous kinase domains and have important roles in many cellular processes (e.g., proliferation, gene expression, metabolism, motility, membrane transport, apoptosis, etc.); unsurprisingly, their misregulation often results in disease. Most eukaryotic protein kinases are members of the eukaryotic protein kinase superfamily. The kinase domain of protein kinases (250–300 amino acids) contains 12 conserved subdomains. The crystal structure of eukaryotic protein kinases shows that they have a bilobed structure (the smaller N-terminal lobe and the larger C-terminal lobe). The deep cleft between the two lobes is recognised as the site of catalysis. Three functions are attributed to the kinase domain: (i) binding and orientation of the ATP (or GTP) phosphate donor as a complex with the divalent cation; (ii) binding and orientation of the protein substrate; and (iii) transfer of the γ-phosphate from the ATP to the hydroxyl residue of the protein substrate 1, 2. In 1995, Hanks and Hunter proposed the first classification of eukaryotic protein kinases, based on their structural and functional properties [2]. In 2002, the classification was refined by Manning et al. based on the extracatalytic sequence similarity and biological function [3]. Several protein kinases lack sequence similarity with eukaryotic protein kinases and, thus, have been classified as inactive pseudokinases [3].