PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc

Abstract

Neuroblastoma is a severe childhood disease, accounting for ~10% of all infant cancers. The amplification of the MYCN gene, coding for the N-Myc transcription factor, is an essential marker correlated with tumor progression and poor prognosis. In neuroblastoma cells, the mitotic kinase Aurora-A (AURKA), also frequently overexpressed in cancer, prevents N-Myc degradation by directly binding to a highly conserved N-Myc region. As a result, elevated levels of N-Myc are observed. During recent years, it has been demonstrated that some ATP competitive inhibitors of AURKA also cause essential conformational changes in the structure of the activation loop of the kinase that prevents N-Myc binding, thus impairing the formation of the AURKA/N-Myc complex. In this study, starting from a screening of crystal structures of AURKA in complexes with known inhibitors, we identified additional compounds affecting the conformation of the kinase activation loop. We assessed the ability of such compounds to disrupt the interaction between AURKA and N-Myc in vitro, using Surface Plasmon Resonance competition assays, and in tumor cell lines overexpressing MYCN, by performing Proximity Ligation Assays. Finally, their effects on N-Myc cellular levels and cell viability were investigated. Our results identify PHA-680626 as an amphosteric inhibitor both in vitro and in MYCN overexpressing cell lines, thus expanding the repertoire of known conformational disrupting inhibitors of the AURKA/N-Myc complex and confirming that altering the conformation of the activation loop of AURKA with a small molecule is an effective strategy to destabilize the AURKA/N-Myc interaction in neuroblastoma cancer cells.

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

“…In general, this study demonstrated the ferroptosis-related gene signatures in NB associated with the prognosis and proposed the possibility of the AURKA gene as a prognostic marker in NB, which is consistent with many preclinical studies (Berwanger et al, 2002;Otto et al, 2009;Ramani et al, 2015;Xie et al, 2017;Boi et al, 2021;Roeschert et al, 2021;Nguyen et al, 2022). We call for more attention to AURKA, expecting to open up a new way to treat NB.…”

“…Previous microarray analyses showed that MYCN-amplified NBs had higher levels of AURKA mRNA than nonamplified NBs ( Berwanger et al, 2002 ) and this was confirmed in another study ( Otto et al, 2009 ), which showed that AURKA was not only required for the growth of MYCN-amplified NB cells but also for cells lacking amplified MYCN, which is consistent with the study of Roeschert et al (2021 ). In addition, it has been reported that changing the conformation of the AURKA activation loop with small molecules can effectively disrupt the AURKA /N-myc interaction in NB cancer cells ( Boi et al, 2021 ), and using selinexor and the AURKA inhibitor alisertib to synergistically increase the cytotoxicity of p53-mediated high-risk NB has potential therapeutic benefits ( Nguyen et al, 2022 ). As a result, we believe that AURKA may open up new avenues for biomarkers used in the prognosis of NB.…”

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

“…It is also important to note the recurring phenomenon in which transcription of AURKA is regulated by some factors that AURKA engages with in protein-protein interactions, such as p53 [86], HIF1 [87], EGFR [88], Myc and FOXM1 [7] (figure 1). This suggests the presence of uncharted regulatory feedback loops, the exploration of which may reveal integrative circuits that control critical cellular functions, in addition to being exploited for therapeutic purposes [89,90].…”

The Essential Oil from Oliveria decumbens Vent. (Apiaceae) as Inhibitor of Breast Cancer Cell (MCF-7) Growth

“…The poor prognosis of cancer patients is related to the over-expression of AURKA. Thus, AURKA is regarded as a target for cancer treatment [ 41 , 42 ]. The development of AURKA inhibitors has become a major challenge in cancer treatment [ 43 ].…”