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  • Introduction Mitotic kinases play an essential role in


    Introduction Mitotic kinases play an essential role in mitosis, Aurora and other mitotic kinases are often observed over-expression in human solid and many hematologic cancers. As one of serine/threonine kinases, Aurora kinase family is involved in centrosome maturation, mitotic spindle formation, chromosome segregation and cytokinesis during mitosis.2, 3 The family includes three kinases designated as Aurora A (AurA), B (AurB) and C (AurC), which possess a carboxy-terminal catalytic domain and an amino-terminal regulatory domain4, 5, 6, 7However, these kinases have quite different and nonoverlapping functions in mitotic processes. AurA increases during late G2 to M phase, and it is involved in centrosome maturation, centrosome separation, bipolar-spindle assembly and other mitotic events9, 10, 11 AurB is located at chromosome 17p13.1, and it is essential for chromosome segregation and execution of cytokinesis. AurC is a chromosomal passenger protein, which appears to have overlapping functions with AurB during mitotic cell division process. Aurora kinases have become a promising anticancer targets since they are related to oncogenesis and tumor progression, and many small molecule Aurora kinases inhibitors have been developed including VX-680, AT9283, AZD1152 and AMG900 (Fig. 1). VX-680 is the first generation of Aurora kinase inhibitor, which blocks cell-cycle progression and induces apoptosis in human tumor. Crystal structure for VX-680 in complex with Aurora kinases show that it occupies the ATP-binding site in Aurora kinases to inhibit catalytic activity.15, 16 AT9283 is a benzimidazole derivative, which suppresses growth and survival in HCT116 O-propargyl-puromycin and produced the polyploid phenotype by inhibiting AurB kinase. AZD1152, a quinazoline derivative, is a selective inhibitor of AurB kinase and displays striking activity in vivo. AMG900 is potent pan-Aurora kinase inhibitor, which belongs to phthalazine derivative. It inhibits autophosphorylation of AurA and pHisH3 on Ser10 in vitro and suppresses the growth of human tumor xenografts in vivo. Phthalazinones exhibited broad activities, such as antihypertensive, antifungal effect, Histamine H1 receptor antagonist and bradykinin B1 receptor antagonist. Prime et al. replaced phthalazine with phthalazinone scaffolds and found phthalazinone is an important pharmacology core for Aurora kinases. Compound 1 is a phthalazinone derivative and the crystal structure for 1 in complex with Aurora kinases show that the amino-pyrazole of 1 can form hydrogen bounds with the hinge region of Aurora A, and the benzyl of 1 may form hydrophobic interaction with Aurora kinases. However, basis on crystal structure analysis, we considered that the benzyl of 1 was too small to completely occupy the hydrophobic pocket of Aurora kinases, which might accommodate a larger group. Herein, we designed and synthesized a series of 2,4-disubstited phthalazinones (Fig. 2) by optimizing N-2 and C-4 fragments as Aurora kinase inhibitors, and evaluated their activities in human tumor cell lines.
    Results and discussion
    Conclusions In summary, we described a series of 2,4-disubstited phthalazinones small molecule inhibitors that showed potent cytotoxicity against the human tumor cell lines. Furthermore, we specifically found that compound 12c inhibited Aurora kinases by decreasing phosphorylation of AurA on Thr288 and AurB on Thr232. Additionally, treatment with compound 12c also resulted G2/M accumulation via the cell-cycle regulators cyclin B1 and cdc2 in HeLa cells. Taken together, compound 12c is a potential anticancer agent by targeting Aurora kinase.
    Acknowledgments We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21672093 and 21372110).
    During the last one and a half decades, kinases have become the most important targets in cancer therapy. However, the higher efficiency and lower toxicity of kinase inhibitors can be observed only in a subpopulation of patients with overexpression or mutation of the particular kinase. Such potential targets are the serine-threonine Aurora kinases (A and B), which were proven to play an important role in the regulation of cell division.,