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  • Aurora B is also known as chromosomal passenger protein and

    2024-04-02

    Aurora-B is also known as chromosomal passenger protein and localizes at the chromosome arms and at centromeres during prophase. As cell cycle continues, Aurora-B moves towards the inner centromere region followed by the central spindle and cortex during amyloid and finally accumulates in the midbody in telophase [16], [17], [18], [19], [20], [21]. Aurora-B with co-factors viz inner centromere protein (INCENP), borealin and survivin forms chromosomal passenger complex [22]. Aurora-B inhibition leads to a failure to bi-orientate chromosomes, perturbed cytokinesis in cell culture. Due to this inhibition, it creates polyploidization and cell death in p53-proficient as well as deficient cells [23], [24], [25], [26]. Aurora-C expression is limited to the testis. Aurora-C can reform Aurora-B functions in Aurora-B-depleted cells signifying that Aurora-C can carry out mitotic functions [23], [24], [25]. These functions are limited to meiosis and overexpressed Aurora-C binds and co-localizes with INCENP and survivin in mitotic cells [27], [28], [29], [30]. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials till date. We have reported details of small molecules, specifically inhibiting all three types of Aurora kinases, which includes extensive literature search in various database like various scientific journals; patents, scifinder and pubMed database; internet resources, books, etc. IC50 values of tumor growth inhibition, in-vitro and in-vivo activity along with clinical trial data are addressed as shown in Fig. 1.
    Aurora-A small molecule inhibitors Following section contains various molecules reported as specific Aurora-A kinase inhibitors (Structure of compounds 1 to 21 are shown in Fig. 2). Song et al. synthesized a novel series of 3-(pyrrolopyridin-2-yl)indazole derivatives and evaluated on five human cancer cell lines. Compound 1 demonstrated IC50 values of 8.3 nM and 1.3 nM against HL60 and HCT-116 cell lines, respectively. For exploring the molecular target, compound 1 was further selected to evaluate the inhibitory activities against a panel of kinases. Finally, it was found active on Aurora-A kinase with significant selectivity at IC50 of 3.2 nM [31]. Luo et al. designed and synthesized N-trisubstituted pyrimidine derivatives and evaluated on multiple cell-lines as cytotoxic agents and as specific Aurora-A inhibitors by in-vitro enzymatic assay method. Compound 2 exhibited good activity with IC50 value of 5 nM. It showed strong growth inhibition in the solid CNE-2 tumor cell and selectively blocked cell-cycle progression at the G2/M phase [32]. Li et al. synthesized a series of N-1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives and screened for anti-proliferative activity. All synthesized compounds showed potent activities against HCT-116 and MCF-7 cancer cell lines and also showed in-vitro Aurora-A kinase enzyme inhibition. Among all synthesized compounds, compound 3 showed most potent inhibitory activity and inhibited the growth of HCT-116 and MCF-7 cell lines with IC50 values of 0.39 ± 0.06 μM and 0.46 ± 0.04 μM, respectively. It showed in-vitro Aurora-A kinase enzyme inhibition with IC50 of 0.16 ± 0.03 μM, which was comparable with the positive control VX-680 having IC50 value of 0.13 ± 0.01 μM [33]. Mohamed et al. synthesized fused pyrimidine scaffold linked with phenyl-sulfonyl moiety, as shown in structure 4. They prepared heterocyclic amine with triethyl ortho-formate in fused pyridine and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity was tested on HCT-116 cells and found active with IC50 value of 0.051 μM [34]. Micheal et al. synthesized phthalazinone derivatives and compound 5 represented a novel Aurora-A inhibitors which proved 1000-fold higher active than Aurora-B. They performed activity on in-vitro Aurora-A enzyme kit and found inhibition at 0.031 μM. Analysis of binding mode of compound 5 indicated interactions with Glu211, Ala213 and Pro214 at hinge region of Aurora-A (PDB:3P9J). In-vitro cytotoxicity study of compound 5 on HCT-116 cell line showed IC50 value of 7.8 μM [35].