Repository logo
 

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

Simple item page
cam.issuedOnline2021-12-04
dc.contributor.authorBoi, Dalila
dc.contributor.authorSouvalidou, Fani
dc.contributor.authorCapelli, Davide
dc.contributor.authorPolverino, Federica
dc.contributor.authorMarini, Grazia
dc.contributor.authorMontanari, Roberta
dc.contributor.authorPochetti, Giorgio
dc.contributor.authorTramonti, Angela
dc.contributor.authorContestabile, Roberto
dc.contributor.authorTrisciuoglio, Daniela
dc.contributor.authorCarpinelli, Patrizia
dc.contributor.authorAscanelli, Camilla
dc.contributor.authorLindon, Catherine
dc.contributor.authorDe Leo, Alessandro
dc.contributor.authorSaviano, Michele
dc.contributor.authorDi Santo, Roberto
dc.contributor.authorCosti, Roberta
dc.contributor.authorGuarguaglini, Giulia
dc.contributor.authorPaiardini, Alessandro
dc.contributor.orcidCapelli, Davide [0000-0002-6716-3854]
dc.contributor.orcidPolverino, Federica [0000-0002-0048-6122]
dc.contributor.orcidMontanari, Roberta [0000-0002-7533-5425]
dc.contributor.orcidTramonti, Angela [0000-0002-5625-1170]
dc.contributor.orcidContestabile, Roberto [0000-0002-5235-9993]
dc.contributor.orcidTrisciuoglio, Daniela [0000-0002-7007-7914]
dc.contributor.orcidLindon, Catherine [0000-0003-3554-2574]
dc.contributor.orcidDe Leo, Alessandro [0000-0001-5596-7217]
dc.contributor.orcidSaviano, Michele [0000-0001-5086-2459]
dc.contributor.orcidDi Santo, Roberto [0000-0002-4279-7666]
dc.contributor.orcidGuarguaglini, Giulia [0000-0002-7541-8183]
dc.contributor.orcidPaiardini, Alessandro [0000-0001-9078-7545]
dc.date.accessioned2021-12-22T15:08:38Z
dc.date.available2021-12-22T15:08:38Z
dc.date.issued2021-12-04
dc.date.updated2021-12-22T15:08:38Z
dc.description.abstractNeuroblastoma 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.
dc.identifier.doi10.17863/CAM.79170
dc.identifier.eissn1422-0067
dc.identifier.issn1661-6596
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331720
dc.languageen
dc.language.isoeng
dc.publisherMDPI AG
dc.publisher.urlhttp://dx.doi.org/10.3390/ijms222313122
dc.subjectAurora-A
dc.subjectN-Myc
dc.subjectPHA-680626
dc.subjectamphosteric inhibitors
dc.subjectneuroblastoma
dc.subjectAdenosine Triphosphate
dc.subjectAntineoplastic Agents
dc.subjectAurora Kinase A
dc.subjectAzepines
dc.subjectBenzazepines
dc.subjectBinding Sites
dc.subjectBinding, Competitive
dc.subjectCell Line
dc.subjectDrug Evaluation, Preclinical
dc.subjectHumans
dc.subjectN-Myc Proto-Oncogene Protein
dc.subjectNeuroblastoma
dc.subjectProtein Conformation
dc.subjectProtein Kinase Inhibitors
dc.subjectPyrazoles
dc.subjectPyrimidines
dc.subjectPyrroles
dc.subjectSurface Plasmon Resonance
dc.titlePHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc.
dc.typeArticle
dcterms.dateAccepted2021-12-01
prism.issueIdentifier23
prism.publicationNameInt J Mol Sci
prism.volume22
pubs.funder-project-idItalian Association for Cancer Research (MFAG 20447)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3390/ijms222313122

Files

Original bundle
Now showing 1 - 3 of 3
No Thumbnail Available
Name:
additional-files.zip
Size:
863.57 KB
Format:
ZIP file
Description:
Supporting information
Licence
https://creativecommons.org/licenses/by/4.0/
Download
Thumbnail Image
Name:
ijms-22-13122.pdf
Size:
1.47 MB
Format:
Adobe Portable Document Format
Description:
Published version
Licence
https://creativecommons.org/licenses/by/4.0/
Download
No Thumbnail Available
Name:
ijms-22-13122.xml
Size:
17.34 KB
Format:
Extensible Markup Language
Description:
Bibliographic metadata
Licence
https://creativecommons.org/licenses/by/4.0/
Download

Collections

Jisc Publications Router