Design strategies, SAR, and mechanistic insight of Aurora kinase inhibitors in cancer

Sankhe, Kaksha; Prabhu, A. Antony Muthu; Khan, Tabassum

doi:10.1111/cbdd.13850

Cited by 17 publications

(11 citation statements)

References 72 publications

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“…Aurora kinase B (AURKB) is present in the centromeres in Prophase and Metaphase and it is located in the central mitotic spindle, being crucial for the segregation of chromosomes and cytokinesis (Zeitlin, Shelby and Sullivan 2001). AURK A and B expressions and kinase activities are elevated in a variety of human cancers and associated with high levels of proliferation and poor prognosis (Sankhe, Prabhu and Khan 2021). AURKB was proposed as a prognosis marker for GBM from a study that showed an overexpression in 25 GBMs samples and a correlation of its expression levels with survival (Zeng et al 2007).…”

Section: )mentioning

confidence: 99%

HeberFERON distinctively targets Cell Cycle in the glioblastoma-derived cell line U-87MG

Miranda

Vázquez-Blomquist

Bringas

et al. 2022

Preprint

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Background HeberFERON is a co-formulation of α2b and γ interferons, based on their synergism, that have shown its clinical superiority over individual interferons in basal cell carcinomas. In Glioblastoma (GBM), HeberFERON has shown promising preclinical and clinical results. This motivated us to design a microarray experiment aimed to identify the molecular mechanisms involved into the distinctive effect of HeberFERON compared with individual interferons. Methods Transcriptional expression profiling including a control (untreated) and three groups receiving α2b-interferon, γ-interferon and HeberFERON was performed using an Illumina HT-12 microarray platform. Unsupervised methods for gene and sample grouping, identification of differentially expressed genes, functional enrichment and network analysis computational biology methods were applied to identify distinctive patterns of HeberFERON action. Validation of most distinctive genes was performed by qPCR. Cell Cycle analysis of cell treated by HeberFERON for 24h, 48h and 72h was carried out by flow cytometry. Results The three treatments show different behavior based on the gene expression profiles. Enrichment analysis identified several Mitotic Cell Cycle related events, in particular from Prometaphase to Anaphase, that are exclusively targeted by HeberFERON. FOXM1 transcription factor network which is involved in several Cell Cycle phases and is highly expressed in GBMs is significantly down regulated by HeberFERON. Flow cytometry experiments corroborated the action of HeberFERON over Cell Cycle in a dose and time dependent manner with a clear cellular arrest since 24h post-treatment. Despite the fact that p53 was not down-regulated by HeberFERON several genes involved in its regulatory activity were functionally enriched. Network analysis also revealed a strong relation of p53 with genes targeted by HeberFERON. We propose a mechanistic model to explain HeberFERON distinctive action, based on the simultaneous activation of PKR and ATF3, p53 phosphorylation changes as well as its reduced MDM2 mediated ubiquitination and export from nucleus to cytoplasm. PLK1, AURKB, BIRC5 and CCNB1 genes, all regulated by FOXM1, also play central roles in this model. These and other interactions could explain a G2/M arrest and the effect of HeberFERON over the proliferation of U-87MG. Conclusions We proposed molecular mechanisms underlying the distinctive behavior of HeberFERON compared to individual interferon treatments, where Cell Cycle related events showed the highest relevance.

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Section: )mentioning

confidence: 99%

HeberFERON distinctively targets Cell Cycle in the glioblastoma-derived cell line U-87MG

Miranda

Vázquez-Blomquist

Bringas

et al. 2022

Preprint

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“…Over the past few decades, intensive research efforts have led to the discovery of chemically diverse categories of Aurora kinase inhibitors. Few of these have translated to clinical trials but their lower efficacy, severe side effects, and increased cytotoxicity in treated patients have limited their success in the clinic. − , There is, however, a renewed interest in Aurora A specific inhibitors because of recent discoveries of its synthetic lethal interactions with various tumor suppressor genes . In this regard, we screened a small library of natural and pseudo (semisynthetic) quinones to identify Aurora-A-specific inhibitors using an Aurora A kinase assay based on the phosphorylation of Aurora-A-substrate TACC3.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

et al. 2022

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Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC 50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin ( 11), potently inhibited the proliferation of various cancer cell lines with IC 50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 μM, respectively. Treatment of cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified quinones as Aurora kinase inhibitors that can serve as a lead for future drug discovery endeavors.

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“…Its fusion inhibition was confirmed morphologically in 293T-ACE2-TMPRSS2 cells at high cell density (Figure 8). MLN8237 is an Aurora serine/threonine kinase inhibitor (Sankhe et al, 2021). It significantly inhibited fusion under all conditions apart from 293T-ACE2 cell fusion at physiological pH (Figure 6, Supplementary Figure S12).…”

Section: Lopsided Kite-shaped Molecules Are Potent Fusion Inhibitorsmentioning

confidence: 97%

Fusion assays for screening of fusion inhibitors targeting SARS-CoV-2 entry and syncytia formation

Chan

2022

Front. Pharmacol.

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Virus fusion process is evolutionarily conserved and provides a promising pan-viral target. Cell-cell fusion leads to syncytial formation and has implications in pathogenesis, virus spread and immune evasion. Drugs that target these processes can be developed into anti-virals. Here, we have developed sensitive, rapid, adaptable fusion reporter gene assays as models for plasma membrane and alternative fusion pathways as well as syncytial fusion in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have confirmed their specificity using neutralizing antibodies and specific protease inhibitors. The fusion report gene assays are more sensitive and unbiased than morphological fusion assay. The fusion assays can differentiate between transmembrane serine protease 2 (TMPRSS2)-dependency in TMPRSS2(+) cells and trypsin-dependency in angiotensin-converting enzyme 2 (ACE2)(+)TMPRSS2(-) cells. Moreover, we have identified putative novel fusion processes that are triggered by an acidic pH with and without trypsin. Coupled with morphological fusion criteria, we have found that syncytia formation is enhanced by TMPRSS2 or trypsin. By testing against our top drug hits previously shown to inhibit SARS-CoV-2 pseudovirus infection, we have identified several fusion inhibitors including structurally related lopsided kite-shaped molecules. Our results have important implications in the development of universal blockers and synergistic therapeutics and the small molecule inhibitors can provide important tools in elucidating the fusion process.

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Design strategies, SAR, and mechanistic insight of Aurora kinase inhibitors in cancer

Cited by 17 publications

References 72 publications

HeberFERON distinctively targets Cell Cycle in the glioblastoma-derived cell line U-87MG

HeberFERON distinctively targets Cell Cycle in the glioblastoma-derived cell line U-87MG

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

Fusion assays for screening of fusion inhibitors targeting SARS-CoV-2 entry and syncytia formation

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