PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc
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 (AUR...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/13122 |
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| author | Dalila Boi Fani Souvalidou Davide Capelli Federica Polverino Grazia Marini Roberta Montanari Giorgio Pochetti Angela Tramonti Roberto Contestabile Daniela Trisciuoglio Patrizia Carpinelli Camilla Ascanelli Catherine Lindon Alessandro De Leo Michele Saviano Roberto Di Santo Roberta Costi Giulia Guarguaglini Alessandro Paiardini |
| author_facet | Dalila Boi Fani Souvalidou Davide Capelli Federica Polverino Grazia Marini Roberta Montanari Giorgio Pochetti Angela Tramonti Roberto Contestabile Daniela Trisciuoglio Patrizia Carpinelli Camilla Ascanelli Catherine Lindon Alessandro De Leo Michele Saviano Roberto Di Santo Roberta Costi Giulia Guarguaglini Alessandro Paiardini |
| author_sort | Dalila Boi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:52:28Z |
| format | Article |
| id | doaj.art-95ae0f8e2a4a42f28065143f67055798 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:28Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-95ae0f8e2a4a42f28065143f670557982023-11-23T02:33:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122231312210.3390/ijms222313122PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-MycDalila Boi0Fani Souvalidou1Davide Capelli2Federica Polverino3Grazia Marini4Roberta Montanari5Giorgio Pochetti6Angela Tramonti7Roberto Contestabile8Daniela Trisciuoglio9Patrizia Carpinelli10Camilla Ascanelli11Catherine Lindon12Alessandro De Leo13Michele Saviano14Roberto Di Santo15Roberta Costi16Giulia Guarguaglini17Alessandro Paiardini18Department of Biochemical Sciences, Sapienza University, 00185 Rome, ItalyDepartment of Biochemical Sciences, Sapienza University, 00185 Rome, ItalyInstitute of Crystallography, National Research Council, Monterotondo, 00015 Rome, ItalyDepartment of Biochemical Sciences, Sapienza University, 00185 Rome, ItalyDepartment of Biochemical Sciences, Sapienza University, 00185 Rome, ItalyInstitute of Crystallography, National Research Council, Monterotondo, 00015 Rome, ItalyInstitute of Crystallography, National Research Council, Monterotondo, 00015 Rome, ItalyInstitute of Molecular Biology and Pathology (IBPM), National Research Council, 00185 Rome, ItalyDepartment of Biochemical Sciences, Sapienza University, 00185 Rome, ItalyInstitute of Molecular Biology and Pathology (IBPM), National Research Council, 00185 Rome, ItalyNerviano Medical Sciences S.r.l.–Oncology, Nerviano, 20014 Milan, ItalyDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKDepartment of Drug Chemistry and Technologies, Pasteur Institut—Cenci Bolognetti Foundation, Sapienza University, 00185 Rome, ItalyInstitute of Crystallography, National Research Council, Monterotondo, 00015 Rome, ItalyDepartment of Drug Chemistry and Technologies, Pasteur Institut—Cenci Bolognetti Foundation, Sapienza University, 00185 Rome, ItalyDepartment of Drug Chemistry and Technologies, Pasteur Institut—Cenci Bolognetti Foundation, Sapienza University, 00185 Rome, ItalyInstitute of Molecular Biology and Pathology (IBPM), National Research Council, 00185 Rome, ItalyDepartment of Biochemical Sciences, Sapienza University, 00185 Rome, ItalyNeuroblastoma 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.https://www.mdpi.com/1422-0067/22/23/13122Aurora-AN-MycneuroblastomaPHA-680626amphosteric inhibitors |
| spellingShingle | Dalila Boi Fani Souvalidou Davide Capelli Federica Polverino Grazia Marini Roberta Montanari Giorgio Pochetti Angela Tramonti Roberto Contestabile Daniela Trisciuoglio Patrizia Carpinelli Camilla Ascanelli Catherine Lindon Alessandro De Leo Michele Saviano Roberto Di Santo Roberta Costi Giulia Guarguaglini Alessandro Paiardini PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc International Journal of Molecular Sciences Aurora-A N-Myc neuroblastoma PHA-680626 amphosteric inhibitors |
| title | PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc |
| title_full | PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc |
| title_fullStr | PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc |
| title_full_unstemmed | PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc |
| title_short | PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc |
| title_sort | pha 680626 is an effective inhibitor of the interaction between aurora a and n myc |
| topic | Aurora-A N-Myc neuroblastoma PHA-680626 amphosteric inhibitors |
| url | https://www.mdpi.com/1422-0067/22/23/13122 |
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